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A11. Links and References - Biology

A11.   Links and References - Biology


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  1. Wood, J. et al. Senile hair graying: H2O2-mediated oxidative stress affects human hair color by blunting methionine sulfoxide repair. FASEB Journal. Published online before print February 23, 2009 as doi: 10.1096/fj.08-125435
  2. Kerr, R. A Shot of Oxygen to Unleash the Evolution of Animals. Science 314, 1529 (2006)
  3. Falkowski, P. Tracings Oxygen's Footprint on Life's Metabolic Evolution. Science 311, 1724 (2006)
  4. Kerr, R. The Story of O2, Science. 308, 1730 (2005)
  5. Schriner, S. Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria. Science 308, pg 1909 (2005)
  6. Kujoth, G.C. Mitochondrial DNA Mutations, Oxidative Stress and Apoptosis in Mammalian Aging. Science. 309, pg 481 (2005)
  7. Mattson, M. Pathways towards and away from Alzheimer's disease. Nature. 430, pg 631 (2004)
  8. Marx, J. How cells endure low oxygen. 303, pg 1454 (2004)
  9. Fromme, J.C. Structural basis for removal of adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase. 427, pg 652 (2004).
  10. Cumming, R. Protein Disulfide Bond Formation in the Cytoplasm during Oxidative Stress. J. Biol. Chem., 279, 21749 (2004)
  11. Darwin, K. Nathan, C. The proteasome of mhycobacterium tuberculosis is required for resistance to nitric oxide. 302, pg 1963 (2003)
  12. Wentworth, P. Evidence for Ozone Formation in human atherosclerotic arteries. 302, pg 1053 (2003)
  13. Neumann et al. Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumor suppression. 424, pg 561 (2003)
  14. Murphy, C. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. 424, pg 277 (2003)
  15. Wentworth, P. Evidence for Antibody-Catalyzed Ozone formation in bacterial killing and inflammation. 298, pg 2195, 2143 (2002)
  16. Wentworth et al. Antibodies Kill by Producing Ozone. 298, pg 1319 (2002); www.sciencemag.org/cgi/content/abstract/1077642.
  17. Lin et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. 418, pgs. 287 , 344 (2002) (counterintuitive finding that increased O2 consumption which leads to increased free radical production doesn't decrease lifespan)
  18. Wentworth et. al. Antibody Catalysis of Oxidation of Water. Science: 293, pg 1806 (2001)
  19. Catling et al. The Rise of Atmospheric Oxygen. 293, pg 819, 839 (2001)
  20. Lee et al. Vitamin C-Induced Decomposition of Lipid Hydroperoxides to Endogeneous Genotoxins. 292, pg 2083 (2001)
  21. Prinn etl al. Evidence for Substantial Variations of Atmospheric Hydroxyl Radicals in the Past Two Decades. 292. pg 1882 (2001)
  22. Finkel & Holbrook. Oxidants, Oxidative Stress and the Biology of Aging. 408. pg 239 (2000)
  23. Oxygenating the atmosphere. 410. pg 317 (2001)
  24. The Story of O Nature. pg 862 (2001)
  25. Kirkwood and Austad. Why Do We Age? Nature. 408, pg 233 (2000)
  26. Xiong et al. When did photosynthesis emerge on Earth? Science. 289. pg 1702or3, 1724 (2000)
  27. Salvemini et al. A Nonpeptidyl mimic of superoxide dismutatse with therapeutic activity in rats. 286. pg 304 (1999)
  28. Head et al. Bioluminescence illuminated (strucure of aequorin - calcium activated photoprotein) Nature 405, pg 291, 372 (2000)
  29. Chipping Away at the Causes of Aging (use microarrays to study gene expression in fibroblasts from normal people and patients with progeria). 287, pg 2390, 2486 (2000)
  30. Lee et al. Gene Expression profile of aging and its retardation by caloric restriction. 295, pg 1390 (1999)
  31. Early Life thrived despite earthly travails. 284, pg 2111 (1999)
  32. Marshall et al. Nitrosation and oxidation in the regulation of gene expression. (post-translational oxidation of transcription factors- possibly at thol residues - might regulate gene expression. 14, pg 1889 (2000)

Articles by OLAW Staff and References

Disclaimer:
OLAW develops and monitors, as well as exercises compliance oversight relative to the Public Health Service Policy on Humane Care and Use of Laboratory Animals (the "PHS Policy"). One of OLAW's primary functions is to advise awarding units and awardee institutions concerning the implementation of the PHS Policy. OLAW often provides this advice by responding to policy-related questions submitted by such units and institutions. The following Articles provide guidance that represents OLAW's current thinking on these topics. This guidance is based on OLAW's experience with the subject matter and draws on best practices followed by the biomedical community regarding the use of research animals. Unless specific statutory or regulatory requirements are cited, the Articles should be viewed as recommendations in that an institution may use an alternative approach if the approach satisfies the requirements of the PHS Policy.


Working with Formulas

Now we can work with some simple formulas. In Excel, you can perform mathematical operations on cells, and copy these formulas to repeat the operations. You must always start by entering the "=" sign to let Excel know that you are doing math (even though that is what it was designed for). The symbols for addition and subtraction are "+" and "-" respectively, as you might suspect. The symbol for multiplication is an asterisk ("*"), and you use a forward slash ("/") for division.

To raise the value of a cell to an exponent, the caret ("^") is used. For example, to square the value of cell A2, you would type in:

Note that you do not have to use upper-case letters to denote columns. As an alternative to typing in the cell coordinates, you also can click on the cell that you want to reference with the cursor after you have typed the " Sheet 1" tab at the bottom of the sheet to return to your original spreadsheet.

In cell B2, type the formula shown above to square the value in cell A2, and hit enter. Now click on cell B2 again. Notice that there is a border around the cell, with a dark square in the bottom right corner:

Click on that square, and drag down the column for each cell adjacent to a value in column A, and then let go of the mouse button. You will see that in column B is now filled with values corresponding to the squared values in column A.

Now click on cell B11, and hit "F2" (one of the function keys at the top of your keyboard). It will show you the formula in the cell and place a color coded box to show you the cell referenced by the formula. It also shows you the formula in the formula bar at the top of the page (red arrow):

The function key "F2" will allow you to see the reference cells for the formulas, and also allow you to edit your formulas. Note that when copying formulas, it is the frame of reference, i.e., where the referenced cells position is relative to the cell where the formula is, that is important, not the actual row or column designation, or what sheet you are on. To demonstrate this, highlight all the cells in column B that have numerical values, copy them (using Ctrl+C), and then paste them in column C by clicking on cell C2, using Ctrl+V. The values are now the squared values from column B.

There will be circumstances, however, where you don't want the reference point of a formula to change when you copy the formula. In these cases, you can anchor a row, or column, or both, using the dollar sign ($)

We will demonstrate the function of the $ anchor by introducing a new Excel function, which gives you the sum of a row or column of cells. Not surprisingly, the name of the function is "SUM".

Click on the "Sheet 2" tab at the bottom of the page to shift to the second worksheet. In cell A13, type the following:

[Note: the period is a shortcut for typing a colon. If the formula does not work, use a colon instead of a period]

Again, as an alternative to typing the cell coordinates, you can highlight the cells that you want the sum of after you have typed the left parenthesis. Hit "Enter", and you will see the sum of the values in column A. Now, drag that formula over to cell B13, using the same technique that you used to copy the formula that squared the values in column A on sheet 1. That value should be zero because there are no values in the corresponding cells. Use F2 to see the cells referenced in the formula to verify this.

Now we will make use of the anchor symbol, which keeps the reference from changing when formulas are copied. In cell B2, type the following:

Notice that you get the same value as you got in A13, because it is the same formula with the same references. Notice also that the value in cell B13 has changed. This is an important feature. Because the value for B13 is determined by a formula, changing a value in one of the reference cells will change the value for B13. This is useful in that correcting an error made at the beginning of a set of calculations will carry that correction through all subsequent calculations, so that you don't have to start over. It can also be dangerous if you make changes as part of a second set of calculations, as the values for the first set will all be changed.

Now drag the formula in B2 down through B11.

Question 1: Why do the values in column B first increase, and then decrease? (Use F2 to help discover what happened)

In cell C2, type the following:

Drag the formula down to C11, then copy column C to column D by highlighting the cells in column C and using Ctrl-C to copy and Ctrl-V to paste, or by highlighting the cells, and dragging to the next column.

Question 2: Why are the values in column D the same as in column C? What did placing the dollar sign in front of the column letter tell Excel to do? (Again, using F2 to view the references will help)

In cell E2, type the following:

Drag the formula down to E11. Now you see a different set of values.

Question 3: Explain what this placement of the anchor told Excel to do.

Lastly, type the following into cell F2, and drag it down to cell F11:

Question 4: Based on the results you obtained for columns C through F, provide a general explanation of the function of the anchor symbol ($), and how its placement affects formula references when formulas are copied.

Before moving on to graphing, we will cover one more useful function. In cell A14, type the following:

Once again, you may use the cursor to highlight the referenced cells instead of typing in the boundaries of the series. Copy this formula to cell B14 by dragging.This will change some of the values in the other columns because of the errant references in those formulas. Don't let it concern you! Just take it as a demonstration that when working with formulas, you need to be aware that changes can have downstream consequences.

Question 5: How does the COUNT function differ from the SUM function?


Annexin A11

This gene encodes a member of the annexin family, a group of calcium-dependent phospholipid-binding proteins. Annexins have unique N-terminal domains and conserved C-terminal domains, which contain the calcium-dependent phospholipid-binding sites. The encoded protein is a 56-kD antigen recognized by sera from patients with various autoimmune diseases. Transcript variants encoding the same isoform have been identified. [7]

ANXA11 has been shown to interact with PDCD6 [8] and ALG2. [9]

It is shown that over-expression of the ANXA11 is involved in apoptotic alterations in schizophrenia and contribute to pathomechanisms of this disorder. [10]

  1. ^ abcGRCh38: Ensembl release 89: ENSG00000122359 - Ensembl, May 2017
  2. ^ abcGRCm38: Ensembl release 89: ENSMUSG00000021866 - Ensembl, May 2017
  3. ^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^
  5. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  6. ^
  7. Misaki Y, Pruijn GJ, van der Kemp AW, van Venrooij WJ (Feb 1994). "The 56K autoantigen is identical to human annexin XI". The Journal of Biological Chemistry. 269 (6): 4240–6. PMID7508441.
  8. ^
  9. Morgan RO, Bell DW, Testa JR, Fernandez MP (Feb 1998). "Genomic locations of ANX11 and ANX13 and the evolutionary genetics of human annexins". Genomics. 48 (1): 100–10. doi:10.1006/geno.1997.5148. PMID9503022.
  10. ^ ab
  11. "Entrez Gene: ANXA11 annexin A11".
  12. ^
  13. Satoh H, Shibata H, Nakano Y, Kitaura Y, Maki M (Mar 2002). "ALG-2 interacts with the amino-terminal domain of annexin XI in a Ca(2+)-dependent manner". Biochemical and Biophysical Research Communications. 291 (5): 1166–72. doi:10.1006/bbrc.2002.6600. PMID11883939.
  14. ^
  15. Satoh H, Nakano Y, Shibata H, Maki M (Nov 2002). "The penta-EF-hand domain of ALG-2 interacts with amino-terminal domains of both annexin VII and annexin XI in a Ca2+-dependent manner". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1600 (1–2): 61–7. doi:10.1016/S1570-9639(02)00445-4. PMID12445460.
  16. ^
  17. Ghazaryan H (Jul 2013). "Annexin 11 expression pattern in schizophrenia". Electronic Journal of Natural Sciences. 21 (2): 74–76.
  • Minami H, Tokumitsu H, Mizutani A, Watanabe Y, Watanabe M, Hidaka H (Jul 1992). "Specific binding of CAP-50 to calcyclin". FEBS Letters. 305 (3): 217–9. doi: 10.1016/0014-5793(92)80671-3 . PMID1299619. S2CID41323727.
  • Dawson SJ, White LA (May 1992). "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". The Journal of Infection. 24 (3): 317–20. doi:10.1016/S0163-4453(05)80037-4. PMID1602151.
  • Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
  • Sjölin C, Dahlgren C (Jun 1996). "Isolation by calcium-dependent translation to neutrophil-specific granules of a 42-kD cytosolic protein, identified as being a fragment of annexin XI". Blood. 87 (11): 4817–23. doi: 10.1182/blood.V87.11.4817.bloodjournal87114817 . PMID8639854.
  • Brownawell AM, Creutz CE (Aug 1997). "Calcium-dependent binding of sorcin to the N-terminal domain of synexin (annexin VII)". The Journal of Biological Chemistry. 272 (35): 22182–90. doi: 10.1074/jbc.272.35.22182 . PMID9268363.
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
  • Sudo T, Hidaka H (Feb 1999). "Characterization of the calcyclin (S100A6) binding site of annexin XI-A by site-directed mutagenesis". FEBS Letters. 444 (1): 11–4. doi: 10.1016/S0014-5793(99)00014-9 . PMID10037139. S2CID25762914.
  • Bances P, Fernandez MR, Rodriguez-Garcia MI, Morgan RO, Fernandez MP (Oct 2000). "Annexin A11 (ANXA11) gene structure as the progenitor of paralogous annexins and source of orthologous cDNA isoforms". Genomics. 69 (1): 95–103. doi:10.1006/geno.2000.6309. PMID11013079.
  • Satoh H, Shibata H, Nakano Y, Kitaura Y, Maki M (Mar 2002). "ALG-2 interacts with the amino-terminal domain of annexin XI in a Ca(2+)-dependent manner". Biochemical and Biophysical Research Communications. 291 (5): 1166–72. doi:10.1006/bbrc.2002.6600. PMID11883939.
  • Satoh H, Nakano Y, Shibata H, Maki M (Nov 2002). "The penta-EF-hand domain of ALG-2 interacts with amino-terminal domains of both annexin VII and annexin XI in a Ca2+-dependent manner". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1600 (1–2): 61–7. doi:10.1016/S1570-9639(02)00445-4. PMID12445460.
  • Breen EC, Tang K (Mar 2003). "Calcyclin (S100A6) regulates pulmonary fibroblast proliferation, morphology, and cytoskeletal organization in vitro". Journal of Cellular Biochemistry. 88 (4): 848–54. doi:10.1002/jcb.10398. PMID12577318. S2CID23949602.
  • Tomas A, Moss SE (May 2003). "Calcium- and cell cycle-dependent association of annexin 11 with the nuclear envelope". The Journal of Biological Chemistry. 278 (22): 20210–6. doi: 10.1074/jbc.M212669200 . PMID12601007.
  • Farnaes L, Ditzel HJ (Aug 2003). "Dissecting the cellular functions of annexin XI using recombinant human annexin XI-specific autoantibodies cloned by phage display". The Journal of Biological Chemistry. 278 (35): 33120–6. doi: 10.1074/jbc.M210852200 . PMID12805373.
  • Tomas A, Futter C, Moss SE (Jun 2004). "Annexin 11 is required for midbody formation and completion of the terminal phase of cytokinesis". The Journal of Cell Biology. 165 (6): 813–22. doi:10.1083/jcb.200311054. PMC2172404 . PMID15197175.
  • Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID16189514. S2CID4427026.

This article on a gene on human chromosome 10 is a stub. You can help Wikipedia by expanding it.


An HLA-A11-specific motif in nonamer peptides derived from viral and cellular proteins.

T lymphocytes recognize their antigenic targets as peptides associated with major histocompatibility complex molecules. The HLA-A11 allele, a preferred restriction element for Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocyte responses, presents an immunodominant epitope derived from the EBV nuclear antigen 4. Subpicomolar concentrations of a synthetic nonamer peptide, IVTDFSVIK, corresponding to amino acids 416-424 of the EBV nuclear antigen 4 sequence, can sensitize phytohemagglutinin-stimulated blasts to lysis by EBV-specific HLA-A11-restricted cytotoxic T-lymphocytes. We show that micromolar concentrations of this peptide induce assembly and surface expression of HLA-A11 in an A11-transfected subline of the peptide transporter mutant cell line T2. Using the IVTDFSVIK peptide and a series of synthetic nonamer peptides, differing from the original sequence by single amino acid substitutions, we have defined a motif for HLA-A11-binding peptides. This predicts the presence of a hydrophobic amino acid in position 2, amino acids with small side chains in positions 3 and 6, and a lysine in position 9. Using this motif, we have identified a peptide in the carboxyl-terminal end of wild-type p53, ELNEALELK, which is able to induce HLA-A11 assembly as efficiently as the IVTDFSVIK viral peptide.


Overview of Identification of Ferroptosis

In 2012, the concept of ferroptosis was first described by Scott J. Dixon (a member of the Brent R. Stockwell group) and his collaborators who described the characteristics of ferroptosis (3). Ferroptosis, a novel type of regulated cell death (RCD), is a unique form of intracellular iron-dependent peroxidation of PUFA-containing phospholipids (PLs), and is morphologically, biochemically, and genetically distinct from other forms of RCD including apoptosis, autophagy, and necroptosis. Cells undergoing ferroptosis show unique hallmarks including rupture of cellular membranes, smaller mitochondria with increased mitochondrial membrane density, reduced/vanished mitochondria cristae, rupture of outer mitochondrial membranes, and a normal nucleus (29).

Early Studies Related to Ferroptosis

In 1955, Eagle et al. first found that human uterine carcinoma HeLa cells cultured without cystine exhibited a unique microscopic morphology that was different than that resulting from deprivation of other amino acids (30). They also found that cells cultured in cystine-free medium failed to grow but could be restored by supplementing them with glutathione (GSH) (31, 32). In 1977, Bannai et al. showed that cystine starvation of human lung fibroblasts resulted in rapid reduction of GSH and subsequent cell death however, cell death could be rescued by the addition of the lipophilic antioxidant α-tocopherol (a component of vitamin E) (33). These results implied that cystine could sustain the intracellular level of GSH and that there might be an accumulation of reactive oxygen species (ROS) that could be prevented by lipophilic antioxidants.

In 1965, two separate research teams both identified lipid peroxidation as a prime cause of cellular damage in rat liver (34, 35). In the 1980s, lipid peroxidation was considered to be one of the main forms of oxidative damage via the destruction of unsaturated lipid components of cell membranes and lipoproteins in some pathologies (36, 37). Nonetheless, these discoveries were considered as mechanisms of cellular damage at that time.

Conceptualization of Ferroptosis

Brent R. Stockwell and members tried to screen small molecules that could selectively kill cells overexpressing the oncogenic mutant HRAS. In 2003, they identified a novel compound that they named 𠇎rastin”, and explored the effect of erastin in engineering tumor cells. However, they found that no characteristics of apoptosis occurred, such as caspase activation, cleavage of caspase substrates, annexin V staining, and morphological changes in the nucleus (38). In 2007, they further reported that erastin induced the formation of oxidative species and subsequent death through an oxidative nonapoptotic mechanism, and that the cell death induced by erastin could be suppressed by α-tocopherol (39). In 2008, they reported yet another small compound, Ras selective lethal 3 (RSL3), which induced a similar iron-dependent non-apoptotic cell death in oncogenic RAS-harboring cancer cells, which could also be suppressed by both α-tocopherol and desferrioxamine mesylate (DFOM) (40). In 2011, the authors distinguished erastin- and RSL3-induced cell death from the mechanism of action of other cell death inducers (41). In 2012, they named this phenomenon of erastin-induced iron-dependent cell death as ferroptosis (3).


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Domains and Repeats

Feature keyPosition(s)Description Actions Graphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/family%5Fand%5Fdomains%5Fsection">Family and Domains</a> section describes the position and type of a domain, which is defined as a specific combination of secondary structures organized into a characteristic three-dimensional structure or fold.<p><a href='/help/domain' target='_top'>More. </a></p> Domain i 30 – 134 Cadherin 1 PROSITE-ProRule annotation

<p>Manual validated information which has been generated by the UniProtKB automatic annotation system.</p> <p><a href="/manual/evidences#ECO:0000255">More. </a></p> Manual assertion according to rules i

Manual assertion according to rules i

Manual assertion according to rules i

Manual assertion according to rules i

Manual assertion according to rules i

Manual assertion according to rules i

Region

Feature keyPosition(s)Description Actions Graphical viewLength
<p>This subsection of the 'Family and Domains' section describes a region of interest that cannot be described in other subsections.<p><a href='/help/region' target='_top'>More. </a></p> Region i 805 – 844 Disordered Sequence analysis

<p>Information which has been generated by the UniProtKB automatic annotation system, without manual validation.</p> <p><a href="/manual/evidences#ECO:0000256">More. </a></p> Automatic assertion according to sequence analysis i

Automatic assertion according to sequence analysis i

Keywords - Domain i

Phylogenomic databases

evolutionary genealogy of genes: Non-supervised Orthologous Groups

The HOGENOM Database of Homologous Genes from Fully Sequenced Organisms

InParanoid: Eukaryotic Ortholog Groups

Identification of Orthologs from Complete Genome Data

Database of Orthologous Groups

Database for complete collections of gene phylogenies

TreeFam database of animal gene trees

Family and domain databases

Integrated resource of protein families, domains and functional sites

Pfam protein domain database

Protein Motif fingerprint database a protein domain database

Simple Modular Architecture Research Tool a protein domain database

Superfamily database of structural and functional annotation

PROSITE a protein domain and family database


RNA granules take a ride on lysosomes

Localized protein synthesis requires intracellular RNA transport, whereby mRNAs are trafficked within RNA granules — membraneless organelles that form through liquid–liquid phase separation. The mechanisms involved in this transport are poorly understood. Liao et al. now show that in mammalian cells, RNA granules are trafficked by ‘hitchhiking’ on lysosomes.

The authors established that in the human U2OS cell line and in primary rat cortical neurons RNA granules associate with the surface of lysosome-like organelles and traffic on them. They then identified annexin A11 (ANXA11) as a protein that interacts with both granules and lysosomes, and thus could serve as a tether between these organelles.

In U2OS cells ANXA11 partitioned to RNA granules in a manner dependent on the N-terminal low-complexity region, which mediates its liquid–liquid phase separation. The interaction with the lysosome, in turn, depended on the C-terminal annexin domains of ANXA11, which bind — in a calcium-dependent manner — to endolysosomal phosphoinositides.

ANXA11 was sufficient to drive association between RNA granules and lysosome-like vesicles in vitro. ANXA11 also co-localized with motile lysosome–RNA granule complexes in neurons, where it was required for unperturbed RNA granule hitchhiking on lysosomes and for efficient RNA delivery to the distal parts of the cell.

Mutations in the gene ANX11 are linked to neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS-causing mutations interfered with phase separation dynamics of ANXA11 and reduced its ability to partition to RNA granules, and also impeded ANXA11 binding to lysosomal membranes. Accordingly, expression of ANXA11 mutants perturbed RNA granule–lysosome contacts, reduced the number of hitchhiking events and interfered with intracellular mRNA transport in neurons, both in culture and in zebrafish larvae.

“ALS-causing mutations interfered with phase separation dynamics of ANXA11”

In summary, efficient mRNA trafficking is supported by tethering of RNA granules to motile lysosomes through ANXA11, which is regulated by phase separation and calcium signalling. Deregulation of these mechanisms could contribute to neurodegeneration.


Review

Annexin family

More than a 100 annexins have been identified in many different species [5]. Twelve proteins have been identified in humans these are conventionally referred to as annexin A1-13 (the ANX-A12 gene is unassigned). The descriptor ‘A’ denotes their presence in vertebrates ‘B’ denotes their presence in invertebrates ‘C’ denotes their presence in fungi and some groups of unicellular eukaryotes ‘D’ denotes their presence in plants and ‘E’ their presence in protists [5, 6]. The zebrafish demonstrates that the annexins are conserved through development. Zebrafish have eleven annexin genes [7] that are expressed in many tissues during embryonic and larval stages. Aligning the zebrafish ANX genes with mammalian ANX genes shows that three zebrafish ANX genes are homologous with human ANX1 two are homologous with human ANX2 and two are homologous with human ANX11. This information suggests that zebrafish ANX genes may have resulted from duplications after the divergence of the zebrafish and mammalian genomes [7].

Human annexin genes

The 12 human annexin genes range in size from 15 kb (ANXA9) to 96 kb (ANXA10) and are spread throughout the genome on chromosomes 1, 2, 4, 5, 8, 9, 10, and 15 [6]. Other vertebral annexin genes may vary slightly in size and chromosomal linkage, but orthologues are similar in their sequence and splicing patterns. It is important that some annexin genes have been lost or duplicated in certain species, such as bony fish and pseudotetraploid frogs [8]. The duplication of annexin genes is also seen in humans [9]. Annexin A6 is a compound gene, probably derived from the fusion of duplicated ANXA5 and ANXA10 genes in early vertebrate evolution. The reasons for the annexin genes or their chromosomal regions to duplicate are not well understood. Their successful preservation and the extent to which they contribute to vertebrate complexity are also not well described [10]. The presence of multiple members of the annexin family in all higher eukaryotes argues for their fundamental role in cell biology.

The ANXA11 gene is located on human chromosome 10q22q23 and is composed of 15 exons and 14 introns without the 5′ flanking region [11]. Exon 1 is the biggest region of the gene and is untranslated. The N-terminal is coded by exons 2 through 5 exons 6–15 are responsible for the C-terminal.

Annexin gene expression levels within human organs have a broad range, from universal (for example, annexins A1, A2, A4, A5, A6, A7, and A11) to selective, such as annexin A3 in neutrophils, annexin A8 in the placenta and skin, annexin A9 in the tongue, annexin A10 in the stomach and annexin A13 in the small intestine [6]. ANXA11 has the highest gene expression in whole blood cells, particularly CD19 + cells (B-cells), CD14 + cells (monocytes) and CD33 + cells (myeloid). However, it is found in almost all tissues including lung, heart, and intestines [12]. Finding high expression of annexin A11 macrophages [13], neutrophils [14] and T-cells [15] suggests it may have a significant role in immune system function and possibly in a number of autoimmune diseases (Fig. 1).

Tissue distribution of annexin A11 gene expression adapted from BioGPS website available at: http://biogps.org/#goto=genereport&id=311

High expression patterns of annexins are detected in thymus, lung, and smooth muscle, and low expression patterns are found in testis, adrenal glands, and brain. The expression of annexins may change with the cell cycle. For instance, while the cell cycle progresses, the distribution of annexin A11 changes. This may be because it is associated with microtubules, vesicle trafficking, and Ca 2+ regulated exocytosis [1, 16, 17].

Protein structures

All annexins share a conserved C-terminal core domain made up of at least four similar repeats, each about 70 amino acids long [18]. These subunits usually contain characteristic ‘type 2′ calcium binding sites. The number and location of these sites generally vary between different annexin families, with variation and replacement with other motifs [5, 19]. Calcium-independent annexin membrane interactions involve a switch from a helix-loop-helix motif to the transmembrane helix, which drives a reversible membrane insertion. This pH-dependent conformation switch can be induced by the protonation of certain carboxylate residues found close to the loop of the helix-loop-helix motif. This model may explain why annexins can span a lipid bilayer [5]. In contrast to the core domain, individual vertebrate annexins have a unique N-terminal domain of variable length, amino acid sequences, and determinants of hydrophobicity. This plays an important role in mediating the interaction of annexins with other intracellular protein partners, such as those of the S100 family cytoplasmic proteins [20]. The NH2-terminal domain of annexin A2 forms a protein-protein interaction through a highly specific binding site for the small dimeric S100 protein S100A10 [21]. This heterotetrameric complex is formed when two annexin A2 molecules are non-covalently linked via a S100A10 dimer bound to their NH2-terminal domains. As a result, this complex can bind simultaneously to two membrane surfaces through its two annexin A2 cores [5].

Nonhuman annexin protein structure has also been studied. The simplest organisms known to express annexins are the protist Giardia lamblia and the fungus Neurospora crassa. The structure of nonhuman annexin protein was discussed elsewhere [22, 23]. Plant annexins have a structure that is distinct from vertebrates. They lack the variable N-terminal domains and type II calcium binding sites [24].

ANXA11 contains 504 amino acids and has a molecular weight of 56 kDa [25]. Its primary structure was purified from rabbit lung in 1992 [26]. ANXA11 has a C-terminal core and a N-terminal head with 50 % homology with other annexin core domains [27]. The C-terminal core contains four domains with calcium binding properties (Fig. 2). Although ANXA11 has not been crystallized yet, its tertiary structure was predicted by information from ANXA1 and ANXA5 [28]. Three isoforms of Annexin A11 are identified in humans, but only one is expressed in cells [29].

Model of the annexin A11 secondary structure with four core domains and a rich tail

Intracellular location and function of annexins

Annexins are usually cytosolic proteins with a soluble and a stable form. Annexins are reversibly associated with components of the cytoskeleton or proteins that mediate interactions between the cell and the extracellular matrix (matri-cellular proteins). Some annexins, such as annexins A11 and A2, have been found in the nucleus under particular circumstances in the cell cycle [16, 17]. It seems that annexin A2 works with annexin A11 in the nucleus. When annexin A2 enters the nucleus, it is rapidly exported to a functional nuclear export (NES) sequence that overlaps the p11-binding region in the annexin 11 N-terminus [21]. When p11 binds to annexin 11, the complex is sequestered in the cytoplasmic compartment [16, 21].

In some circumstances, annexins can be expressed at the cell surface even without a secretory signal peptide. For example, annexin A1 translocates from the cytosol to the cell surface following exposure of cells to glucocorticoids [30]. In a study involving U-937 cells, annexin 1 translocated from the intracellcular compartment to the cell membrane without a signal exporting sequence. The level of expression of annexin 1 was directly related to the time exposed to dexamethasone. Prior to its release, the protein may accumulate in the cell membrane, and this is stimulated by dexamethasone in differentiated U-937 cells [30].

Annexin A2 expression at surface of vascular endothelial cells has a function in the regulation of plasmin generation [31]. It has been shown that Annexin A2 is a co-receptor for tissue plasminogen activator and plasminogen. This expression can be found on a variety of cells, including endothelial cells, tumor cells, and macrophages. This study also showed that Annexin A2 may also have a role in maintaining vascular patency and the cell formation of new blood vessels [31].

Annexin A11 distribution changes per cell cycle. It is more prevalent in the nucleus than the cytoplasm in interphase cells and then moves to degenerating nuclear envelope. And finally during the mitotic phase, it will be concentrated within the central spindle [16]. It has been shown that Annexin A11 also has an essential role in the terminal phase of cytokinesis. Annexin A11 is recruited to the midbody in late telophase, and without Annexin A11, cells cannot establish a functional midbody. [32]. Instead, daughter cells remain connected by intercellular bridges. As a result, these cells without Annexin A11 do not complete cytokinesis and die by apoptosis [32].

Annexins interaction with other proteins

S100 proteins, which only express in vertebrates, are a well-known group of proteins that interact with the annexins. The functions of S100 proteins are diverse and include regulating actin and microtubule networks, promoting cell survival and proliferation, calcium homeostasis, and mediating muscle contraction. The complex of annexin A2-S100A10 interacts with several membrane ion channels, such as transient receptor like potential vanilloid type 5 and 6 channels (TRPV5 and TRPV6). The complex also interacts with cystic fibrosis conductance regulator protein (CFTR) and plays a role the regulation of these ion channels [33, 34]. It is clear that these proteins are involved in a great number of intracellular processes, such as membrane trafficking, organization, and functioning as extracellular local hormones.

Annexin A11 is involved in cellular apoptotic processes. The N-terminal domain of ANXA11 contains binding sites that deliver Ca 2+ to S100A6 and apoptosis-linked gene2 (ALG-2) whose protein augments apoptosis. The significance of these interactions in the pathogenesis of sarcoidosis is discussed later in this article.

Association of annexin to diseases in laboratory animal models

Studies on knockout mice of annexin families show a diversity of functions among these proteins. Loss of ANXA1 causes changes in the inflammatory response and the effects of glucocorticoids [35]. In the ANXA1 null mouse line, there was altered expression of other annexins as well as cyclooxygenase-2 and cytoplasmic phospholipase A2. In addition, there was an exaggerated response to the stimuli characterized by an increase in leukocyte emigration and IL-1β generation and a partial or complete resistance to the anti-inflammatory effects of glucocorticoids [35].

Data supports the role of annexin 2 as a regulator of cell surface plasmin generation, fibrin homeostasis, and neovascularization in laboratory mice models [36]. Homozygous annexin 2 knockout mice were studied, and they showed deposition of fibrin in the microvasculature. These null mice also had deficits in the clearance of arterial thrombi and tissue plasminogen activator (T-PA)–dependent plasmin generation at the endothelial cell surface. Also, annexin 2–deficient mice displayed problems with neovascularization of fibroblast growth factor–stimulated cornea and of oxygen-primed neonatal retina [36].

Another study involved the formation of the ANXA7 knockout mouse. The viability of the ANXA7 null mouse was compared to the heterozygous mouse [37]. The ANXA7 null mutation mouse was did not survive past embryonic day 10. This was due to cerebral hemorrhage. On the other hand, the heterozygous mouse, though only expressing low levels of ANXA7, was viable and able to reproduce [37].

Another study of ANXA7 null mutant mouse proposed ANXA7 function in the fusion of vesicles as a calcium channel [38]. Cardiomyocytes from adult ANXA7 null mice were studied. When stimulated with high frequencies, the cells showed an altered cell shortening relationship. Possibly through its role in calcium regulation, this study suggested a function for annexin A7 in electromechanical coupling [38]. The other annexins knockouts need further investigation.

Association of annexin to human diseases

Annexins have essential roles in the pathogenesis or progression of many human diseases. Recent genetic studies discovered single nucleotide polymorphisms (SNPs) in the genomes of this group of proteins. In a study from India, annexin A2 gene SNP (rs7170178) was found to be associated with osteonecrosis in sickle cell patients [39]. The frequency of the ANXA2 gene polymorphism was higher in the sickle cell patients compared to controls. The SNP was also present in higher frequency in sickle cell osteonecrosis patients than those without osteonecrosis [39].

In another study from Japan, the annexin A5 gene polymorphism was found to be associated with recurrent pregnancy loss. The promoter region of the ANXA5 gene was sequenced in 243 Japanese women with recurrent pregnancy loss and 119 fertile controls [40]. In a case control study for six common ANXA5 gene SNPs, the carrier frequency for the minor allele was significantly higher in the pregnancy loss group [40]. For SNP5, women with this minor allele had a two-fold higher risk of fetal loss than non- carriers. Homozygotes for the SNP5 minor allele had a seven-fold higher risk of recurrent pregnancy loss [40].

Annexins are also associated with autoimmune disorders. In rheumatoid arthritis, high extracellular annexin V levels initiates the production of annexin V autoantibodies that may have a crucial role in pathogenesis of disease [41]. Systemic lupus may involve defective clearance of dying cells, resulting in the exposure of nuclear antigens in the form of cellular debris or microparticles. These microparticles may contain antigens that trigger autoimmune processes. Lupus patients have decreased annexin V binding microparticles and an increase in annexin V non-binding microparticles [42].

Dysregulation of Annexin A11 has been found in cancer, cancer treatment, and diabetes [43]. For example, Annexin A11 is directly involved in cell proliferation in ovarian cancer [44]. The knockdown of annexin A11 expression reduced cell proliferation and the ability of ovarian cancer cells to form a colony. Silencing of annexin A11 was also associated with cisplatin resistance in ovarian cancer cells. [44, 45]. ANXA2 is also involved in P53-mediated apoptosis of lung cancer cells [46]. It has been shown that drug-resistant small cell lung cancer cells highly express annexin A2. Thus, Annexin A2 may have a role in pathogenicity of drug resistance [47].

Some members of the annexin family may also be used as biomarkers and for clinical imaging. For example, ANXA1 was investigated as a potential serum biomarker for lung cancer. Lung cancer tissues exhibited higher expression of annexin A1 than normal tissues. In addition, increased serum annexin A1 was significantly associated with pathologic grade and clinical stage of lung cancer patients [48]. Quantitative 99 mTc-annexin A5 (qAnx5) imaging uses human annexin A5 radiolabeled for the visualization and measurement of apoptosis. This imaging is being investigated as an objective evaluation of apoptosis before and after cancer treatment. Annexin A5 may be used as clinical imaging marker for treatment response [49].

ANXA11 and sarcoidosis

Sarcoidosis is a systemic immune disorder with a characteristic accumulation of epithelioid granulomas in many organs, such as the lungs, kidney, skin and eyes [50, 51]. Chronic sarcoidosis is disease activity lasting more than 2 years [52, 53]. One of the consequences of chronic sarcoidosis is pulmonary fibrosis [54]. Pulmonary fibrosis occurs in 20 % of patients and contributes significantly to morbidity and mortality among these patients [55–58].

Genetic instability and mutation in annexin A11 has been identified in single nucleotide polymorphisms in patients with sarcoidosis compared to control groups. Decreased activation of CD8 + and CD19 + , immune cells involved in sarcoidosis, are proposed mechanisms for sarcoidosis [15]. In addition to the SNP discovery, sarcoidosis patients show an increase in neutrophil counts in bronchoalveolar lavage fluid. This has led to the investigation of annexin A11, which is important in cell division, apoptosis, and neutrophil function. In a study of more than 440,000 SNPs of 490 German patients with sarcoidosis, a series of genetic associations were detected compared with controls [15]. The strongest association signal maps to the ANXA11 (annexin A11) gene on chromosome 10q22.3. A common nonsynonymous SNP (rs104955) was found to be strongly associated with sarcoidosis. As it is demonstrated in Fig. 3, this SNP causes a substitution of arginine with cysteine at position 230 (R230C). Although the mechanistic effect of this change has not been well defined, it appears to affect apoptosis and proliferation in sarcoidosis [15]. Fillerova and coworkers showed that peripheral blood mononuclear cell (PBMC) isolated from subjects with sarcoidosis who carried the ANXA11 R230C SNP were more resistant to apoptosis than the wild genotype. This association was particularly prominent in subjects with the TT ANXA11 phenotype [59]. The mechanism of this increasing resistance to apoptosis was not discussed. We theorize that ANXA11 with structural changes after SNP R230C loses all or part of its functionality. As mentioned above, ANXA11 carries 4 calcium ions and delivers calcium to many intracellular pathways. ANXA11 is involved in apoptosis in at least two known pathways. As shown in Fig. 4, ANXA11 is involved in mitogen-activated protein kinase (MAPK) and P53 pathways. Mitogen-activated protein kinase pathways are involved in apoptosis in the setting of environmental stress [60]. The MAPK pathway activates caspase pathway via an ALG-2 protein that is Ca 2+ dependent. Without calcium delivery from ANXA11 to ALG-2, the apoptosis via caspase pathway would not be activated [61].

ANXA11 polymorphism in location 230. Created based on this article: Alejandra Tomas and Stephen E Moss J Biol Chem 2003, 278:20210–20216


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