S100A1
Template:PBB S100 calcium-binding protein A1, also known as S100A1, is a protein which in humans is encoded by the S100A1 gene.[1][2]
Function
The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs.[3] S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in stimulation of Ca2+-induced Ca2+ release, inhibition of microtubule assembly, and inhibition of protein kinase C-mediated phosphorylation. Reduced expression of this protein has been implicated in cardiomyopathies.[1]
S100A1 overexpression enhances cardiac contractile performance which suggests that S100A1 is a regulator of myocardial contractility. S100A1 improves cardiac performance both by regulating calcium ion handling by the sarcoplasmic reticulum and the responsiveness of myofibrils to calcium ion.[4]
In melanocytic cells, S100A1 gene expression may be regulated by MITF.[5]
S100A1 structure
Like many other S100 proteins, S100A1 can exist as either a hetero or homodimer. Protein nuclear magnetic resonance spectroscopy structural information on the homodimeric form of this protein shows that each monomer is quite helical, and contains two EF-hand calcium-binding loops; an 'S100' EF hand in the N-terminus and a canonical EF-hand in the C-terminus. These domains are linked by a 'hinge' region, which exists as a random coil. Both EF-hands bind calcium, although the real EF-hand has a significantly higher affinity (with a dissociation constant of roughly 20 micromolar). The two calcium-binding regions neighbor each other in three dimensional space, and are connected to each other through a short beta sheet region (residues 27–29 and 68–70).
The S100A1 homodimer is high affinity (nanomolar range or tighter), and is formed through hydrophobic packing of an X-type 4-helix bundle created between helices 1, 1', 4, and 4'.
Recently the most accurate high-resolution solution structure of human S100A1 protein (PDB accesion code: 2L0P) has been determined by means of NMR spectroscopy (ref. Nowakowski, M., Jaremko, L., Jaremko, M., Zhukov, I., Belczyk, A., Bierzynski, A,. Ejchart, A. Solution NMR structure and dynamics of human apo-S100A1 protein., J. Struct. Biol. 2011, 174, 391-399, doi: 10.1016/j.jsb.2011.01.011).
Conformational change
Upon binding calcium, helix 3 of S100A1 (and most other S100 proteins as well) re-orients from being relatively antiparallel to helix 4 to being roughly perpendicular. This conformational change is different from most EF-hands, in that the entering helix, and not the exiting helix, moves. This conformational change exposes a large hydrophobic pocket between helix 3, 4, and the 'hinge' region of S100A1 that is involved in virtually all calcium-dependent target protein interactions. These biophysical properties seem to be well conserved across the S100 family of proteins. Helix 3, 4, and the hinge region are the most divergent areas between individual S100 proteins, and so it is likely that the sequence of these regions is pivotal in fine-tuning calcium-dependent target binding by S100 proteins.
Interactions
S100 calcium-binding protein A1 has been shown to interact with PGM1,[6] S100B[7][8][9] and S100A4.[7][10]
References
- ^ a b "Entrez Gene: S100A1 S100 calcium binding protein A1".
- ^ Morii K, Tanaka R, Takahashi Y, Minoshima S, Fukuyama R, Shimizu N, Kuwano R (1991). "Structure and chromosome assignment of human S100 alpha and beta subunit genes". Biochem. Biophys. Res. Commun. 175 (1): 185–91. doi:10.1016/S0006-291X(05)81218-5. PMID 1998503.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Marenholz I, Heizmann CW, Fritz G (2004). "S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature)". Biochem. Biophys. Res. Commun. 322 (4): 1111–22. doi:10.1016/j.bbrc.2004.07.096. PMID 15336958.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Most P, Bernotat J, Ehlermann P, Pleger ST, Reppel M, Börries M, Niroomand F, Pieske B, Janssen PM, Eschenhagen T, Karczewski P, Smith GL, Koch WJ, Katus HA, Remppis A (2001). "S100A1: a regulator of myocardial contractility". Proc. Natl. Acad. Sci. U.S.A. 98 (24): 13889–94. doi:10.1073/pnas.241393598. PMC 61137. PMID 11717446.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Hoek KS, Schlegel NC, Eichhoff OM; et al. (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ Landar, A (1996). "Identification of an S100A1/S100B target protein: phosphoglucomutase". Cell Calcium. 20 (3). SCOTLAND: 279–85. doi:10.1016/S0143-4160(96)90033-0. ISSN 0143-4160. PMID 8894274.
{{cite journal}}: Cite has empty unknown parameters:|laydate=,|laysource=, and|laysummary=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help); Unknown parameter|quotes=ignored (help) - ^ a b Rual, Jean-François (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062). England: 1173–8. doi:10.1038/nature04209. PMID 16189514.
{{cite journal}}: Cite has empty unknown parameters:|laydate=,|laysource=, and|laysummary=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help); Unknown parameter|quotes=ignored (help) - ^ Deloulme, J C (2000). "S100A6 and S100A11 are specific targets of the calcium- and zinc-binding S100B protein in vivo". J. Biol. Chem. 275 (45). UNITED STATES: 35302–10. doi:10.1074/jbc.M003943200. ISSN 0021-9258. PMID 10913138.
{{cite journal}}: Cite has empty unknown parameters:|laydate=,|laysource=, and|laysummary=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help); Unknown parameter|quotes=ignored (help)CS1 maint: unflagged free DOI (link) - ^ Yang, Q (1999). "Demonstration of heterodimer formation between S100B and S100A6 in the yeast two-hybrid system and human melanoma". Exp. Cell Res. 246 (2). UNITED STATES: 501–9. doi:10.1006/excr.1998.4314. ISSN 0014-4827. PMID 9925766.
{{cite journal}}: Cite has empty unknown parameters:|laydate=,|laysource=, and|laysummary=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help); Unknown parameter|quotes=ignored (help) - ^ Wang, G (2000). "Interaction in vivo and in vitro of the metastasis-inducing S100 protein, S100A4 (p9Ka) with S100A1". J. Biol. Chem. 275 (15). UNITED STATES: 11141–6. doi:10.1074/jbc.275.15.11141. ISSN 0021-9258. PMID 10753920.
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Both through biochemical and cell culture assays, S100A1 has also been shown to interact with the calmodulin binding region of the ryanodine receptor (RyR), as well as the regulatory subunit of PKA IIb. In addition, multiple drugs, including Pentamidine, Amlexanox, Olopatadine, Cromolyn, and Propanolol, are known to bind to S100A1, although their affinities are often in the mid-micromolar range.
Further reading
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