S100A1

S100A1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2L0P, 2LHL, 2LLS, 2LLT, 2LLU, 2LP2, 2LP3, 2LUX, 2M3W
Identifiers
Aliases	S100A1 , S100, S100-alpha, S100A, S100 calcium-binding protein A1, S100 calcium binding protein A1
External IDs	OMIM: 176940; MGI: 1338917; HomoloGene: 4566; GeneCards: S100A1; OMA:S100A1 - orthologs
Gene location (Human) Chr. Chromosome 1 (human) [1] Band 1q21.3 Start 153,627,926 bp [1] End 153,632,039 bp [1]
Gene location (Mouse) Chr. Chromosome 3 (mouse) [2] Band 3 F1|3 39.24 cM Start 90,418,341 bp [2] End 90,421,699 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in apex of heart right auricle of heart C1 segment muscle of thigh gastrocnemius muscle left ventricle myocardium of left ventricle right frontal lobe thoracic diaphragm amygdala Top expressed in vestibular membrane of cochlear duct transitional epithelium of urinary bladder vestibular sensory epithelium utricle submandibular gland interventricular septum myocardium of ventricle cardiac muscle tissue of left ventricle right ventricle right kidney More reference expression data BioGPS More reference expression data
Gene ontology Molecular function calcium ion binding S100 protein binding protein homodimerization activity ATPase binding calcium-dependent protein binding metal ion binding protein binding identical protein binding Cellular component cytoplasm M band I band sarcoplasmic reticulum Z discdkac neuron projection A band nucleus extracellular region protein-containing complex Biological process intracellular signal transduction regulation of heart contraction substantia nigra development positive regulation of voltage-gated calcium channel activity negative regulation of transcription by RNA polymerase II toll-like receptor signaling pathway positive regulation of nitric-oxide synthase activity positive regulation of sprouting angiogenesis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6271 20193 Ensembl ENSG00000160678 ENSMUSG00000044080 UniProt P23297 P56565 RefSeq (mRNA) NM_006271 NM_011309 RefSeq (protein) NP_006262 NP_035439 Location (UCSC) Chr 1: 153.63 – 153.63 Mb Chr 3: 90.42 – 90.42 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Protein S100-A1, also known as S100 calcium-binding protein A1 is a protein which in humans is encoded by the S100A1 gene. ^{[5] [6]} S100A1 is highly expressed in cardiac and skeletal muscle, and localizes to Z-discs and sarcoplasmic reticulum. S100A1 has shown promise as an effective candidate for gene therapy to treat post-myocardially infarcted cardiac tissue.

Structure

S100A1 is a member of the S100 family of proteins expressed in cardiac muscle, skeletal muscle, and the brain, ^[7] with the highest density at Z-lines and the sarcoplasmic reticulum. ^[8] In its dimerized form, S100A1 contains four EF-hand calcium-binding motifs, ^[9] and can exist as either a heterodimer or a homodimer. The homodimer is a high-affinity complex (nanomolar range or tighter) stabilized by hydrophobic packing within an X-type four-helix bundle formed by helices 1, 1′, 4, and 4′.

Protein nuclear magnetic resonance spectroscopy shows that each monomer is helical and contains two EF-hand loops: one in the N-terminus and a canonical EF-hand in the C-terminus. The C-terminal site has higher calcium affinity, with a dissociation constant of about 20 µM. The two EF-hands are positioned adjacent to each other in three-dimensional space and are linked by a short beta sheet (residues 27–29 and 68–70). Calcium binding triggers a conformational change in helix 3, which reorients from being nearly antiparallel to helix 4 to being roughly perpendicular. This mechanism is atypical among EF-hand proteins because the entering helix moves rather than the exiting one. The rearrangement exposes a large hydrophobic pocket between helices 3, 4, and the hinge region, which mediates most calcium-dependent target interactions.

These structural features are generally conserved across the S100 family, although helices 3, 4, and the hinge region are the most divergent areas. Sequence variation in these regions likely fine-tunes calcium-dependent target binding specificity. ^[10] S-Nitrosylation of Cys85 further modifies the protein by reorganizing the C-terminal helix and the linker connecting the two EF-hands. ^[11] The most accurate high-resolution solution structure of human apo-S100A1 (PDB accession code: 2L0P) was determined by NMR spectroscopy in 2011. ^[12]

In addition to Ca²⁺, S100A1 also binds Zn²⁺. Mass spectrometry and isothermal titration calorimetry show up to four Zn²⁺ ions per monomer, with two high-affinity sites located within the EF-hands and two lower-affinity sites outside them. Zn²⁺ competes with Ca²⁺ at the EF-hands, producing mixed 2Ca²⁺:S100A1:2Zn²⁺ species under saturating conditions. QM/MM modeling suggests that the N-terminal EF-hand favors Zn²⁺, while the C-terminal site can accommodate both metals. Functionally, Ca²⁺ binding increases thermal stability, whereas excess Zn²⁺ destabilizes the protein and promotes aggregation. Despite this, S100A1 remains dimeric across all tested metal concentrations. ^[13]

Function

S100 proteins are localized in the cytoplasm and/or nucleus of many cell types, where they regulate processes such as cell cycle progression and differentiation. S100A1 may contribute to stimulation of Ca²⁺-induced Ca²⁺ release, inhibition of microtubule assembly, and inhibition of protein kinase C-mediated phosphorylation.

During development, S100A1 is expressed in the primitive heart at embryonic day 8 at similar levels in both atria and ventricles. By embryonic day 17.5, expression becomes enriched in the ventricular myocardium and reduced in atrial tissue. ^[14]

S100A1 is a regulator of myocardial contractility. Overexpression in rabbit or murine cardiomyocytes enhances contractile performance by increasing sarcoplasmic reticular Ca²⁺ transients and uptake, modifying myofibrillar Ca²⁺ sensitivity, enhancing SERCA2A activity, and promoting calcium-induced calcium release. ^{[15] [16] [17]} S100A1 increases the gain of excitation-contraction coupling ^[18] and decreases Ca²⁺ spark frequency in cardiomyocytes. ^[19] It also enhances L-type calcium channel-mediated transsarcolemmal influx in a protein kinase A-dependent manner. ^[20] S100A1 also interacts with the PEVK region of Titin in a Ca²⁺-dependent manner, reducing passive force in vitro and suggesting a role in modulating Titin-based passive tension before systole. ^{[21] [22]} In mice lacking S100A1, cardiac reserve under β-adrenergic stimulation is reduced, with impaired contraction and relaxation rates and diminished Ca²⁺ sensitivity, although these animals do not develop cardiac hypertrophy or dilation with age. ^[23]

Clinical significance

Expression changes in disease

S100A1 expression is altered in several pathological contexts. In animal models, protein levels are increased in right ventricular cardiac hypertrophy associated with pulmonary hypertension, ^[24] and in brain, skeletal muscle, and cardiac muscle in type I diabetes mellitus. ^[25] At the transcriptional level, S100A1 helps regulate the genetic program underlying hypertrophy by inhibiting α₁-adrenergic induction of genes such as MYH7, ACTA1, and S100B. ^[26]

Cardiac disease

In humans, reduced myocardial S100A1 expression has been linked to cardiomyopathies. ^[27] Importantly, left ventricular assist device therapy does not restore myocardial S100A1 levels in patients with end-stage heart failure. ^[28]

S100A1 regulates endothelial cell function, where its deficiency impairs post-ischemic angiogenesis. Downregulation has been observed in hypoxic tissue from patients with limb ischemia. ^{[29] [30]} In melanocytic cells, S100A1 expression may also be regulated by MITF. ^[31]

Therapeutic potential

Therapeutic strategies have investigated S100A1 gene transfer. In a rat model of myocardial infarction, intracoronary adenoviral delivery of S100A1 restored Ca²⁺ handling, normalized intracellular sodium, reversed fetal gene expression, preserved contractility, reduced hypertrophy, and improved inotropic reserve. ^{[32] [33]} Similarly, transgenic overexpression of S100A1 in mice subjected to infarction preserved contractility, Ca²⁺ cycling, and β-adrenergic signaling, while preventing hypertrophy, apoptosis, and progression to heart failure, ultimately improving survival. ^{[34] [35]} Gene transfer to engineered heart tissue has also been shown to enhance contractile performance of tissue grafts, suggesting potential applications in regenerative therapy. ^[36]

Biomarker potential

S100A1 has also been studied as a diagnostic and prognostic biomarker. Plasma levels rise early during acute myocardial ischemia, with a distinct timecourse compared to creatine kinase, CKMB, and troponin I. ^[37] After ischemic injury, S100A1 is released from cardiomyocytes and can signal through Toll-like receptor 4 to modulate myocardial damage. ^[38] Extracellular S100A1 also protects neonatal murine cardiomyocytes against apoptosis through ERK1/2-dependent pathways, suggesting that release from injured cells may function as an intrinsic survival mechanism. ^[39] Elevated S100A1 has also been observed during cardiopulmonary bypass, both in infants with cyanotic heart disease undergoing uncontrolled hyperoxic reoxygenation ^[40] and in adults undergoing cardiac surgery. ^[41]

Drug interactions

Several drugs—including Pentamidine, Amlexanox, Olopatadine, Cromolyn, and Propranolol—bind to S100A1, though their affinities are generally in the mid-micromolar range. ^[10]

Research

S100A1 has emerged as a promising therapeutic target in heart failure research. Preclinical studies in large animal models and experiments on failing human cardiomyocytes have demonstrated that restoring S100A1 expression can reverse contractile dysfunction, normalize Ca²⁺ signalling, and improve overall myocardial performance. ^[42] In a large-animal model of post-ischemic heart failure, cardiac-specific delivery of S100A1 via an AAV9 vector restored contractile reserve and prevented adverse remodeling. ^[43] These findings highlight the translational potential of S100A1-based therapy.

S100A1 is a multifaceted therapeutic target that bridges basic cardiac physiology and clinical application. ^{[44] [45] [46] [47]} Collectively, these works propose that S100A1 modulates multiple aspects of cardiac physiology, including excitation–contraction coupling, β-adrenergic signaling, and mitochondrial energy metabolism.

Because of these pleiotropic effects, S100A1 gene therapy has been positioned as a potentially safer and more durable alternative to conventional heart failure drugs, which often target single signaling pathways. Preclinical data suggest that viral-mediated S100A1 delivery not only enhances contractility but also prevents maladaptive hypertrophy, apoptosis, and progression to heart failure. ^[48] Current expert consensus places S100A1-based therapy “on the verge” of early clinical trials, with the potential to become part of a new generation of gene-based strategies for treating advanced heart failure. ^{[49] [50]}

Interactions

S100 interacts with

• PGM1 ^[51]
• S100B ^{[52] [53] [54]}
• S100A4 ^{[52] [55]}
• TRPM3 ^[56]
• Titin ^[21]
• RYR2 ^{[15] [57] [58]}
• SERCA2A ^{[59] [60]}
• PLB ^[59]
• RYR1 ^[61]

References

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57. Wright N, Prosser B, Varney K, Zimmer D, Schneider M, Weber D (26 September 2008). "S100A1 and calmodulin compete for the same binding site on ryanodine receptor". The Journal of Biological Chemistry. 283 (39): 26676–26683. doi: 10.1074/jbc.m804432200 . PMC   2546546 . PMID   18650434.
58. Prosser B, Hernández-Ochoa E, Schneider M (October 2011). "S100A1 and calmodulin regulation of ryanodine receptor in striated muscle". Cell Calcium. 50 (4): 323–331. doi:10.1016/j.ceca.2011.06.001. PMC   3185186 . PMID   21784520.
59. Kiewitz R, Acklin C, Schäfer BW, Maco B, Uhrík B, Wuytack F, et al. (June 2003). "Ca2+ -dependent interaction of S100A1 with the sarcoplasmic reticulum Ca2+ -ATPase2a and phospholamban in the human heart". Biochemical and Biophysical Research Communications. 306 (2): 550–557. doi:10.1016/s0006-291x(03)00987-2. PMID   12804600.
60. Most P, Boerries M, Eicher C, Schweda C, Völkers M, Wedel T, et al. (January 2005). "Distinct subcellular location of the Ca2+-binding protein S100A1 differentially modulates Ca2+-cycling in ventricular rat cardiomyocytes". Journal of Cell Science. 118 (Pt 2): 421–431. doi:10.1242/jcs.01614. PMID   15654019. S2CID   33063596.
61. Prosser B, Wright N, Hernãndez-Ochoa E, Varney K, Liu Y, Olojo R, et al. (22 February 2008). "S100A1 binds to the calmodulin-binding site of ryanodine receptor and modulates skeletal muscle excitation-contraction coupling". The Journal of Biological Chemistry. 283 (8): 5046–5057. Bibcode:2008JBiCh.283.5046P. doi: 10.1074/jbc.m709231200 . PMC   4821168 . PMID   18089560.

Further reading

• Zimmer DB, Cornwall EH, Landar A, Song W (1995). "The S100 protein family: history, function, and expression". Brain Research Bulletin. 37 (4): 417–429. doi:10.1016/0361-9230(95)00040-2. PMID   7620916. S2CID   34720854.
• Schäfer BW, Heizmann CW (April 1996). "The S100 family of EF-hand calcium-binding proteins: functions and pathology". Trends in Biochemical Sciences. 21 (4): 134–140. doi:10.1016/S0968-0004(96)80167-8. PMID   8701470.
• Garbuglia M, Verzini M, Sorci G, Bianchi R, Giambanco I, Agneletti AL, et al. (October 1999). "The calcium-modulated proteins, S100A1 and S100B, as potential regulators of the dynamics of type III intermediate filaments". Brazilian Journal of Medical and Biological Research. 32 (10): 1177–1185. doi: 10.1590/s0100-879x1999001000001 . PMID   10510252.
• Engelkamp D, Schäfer BW, Erne P, Heizmann CW (October 1992). "S100 alpha, CAPL, and CACY: molecular cloning and expression analysis of three calcium-binding proteins from human heart". Biochemistry. 31 (42): 10258–10264. doi:10.1021/bi00157a012. PMID   1384693.
• Morii K, Tanaka R, Takahashi Y, Minoshima S, Fukuyama R, Shimizu N, et al. (February 1991). "Structure and chromosome assignment of human S100 alpha and beta subunit genes". Biochemical and Biophysical Research Communications. 175 (1): 185–191. Bibcode:1991BBRC..175..185M. doi:10.1016/S0006-291X(05)81218-5. PMID   1998503.
• Baudier J, Glasser N, Gerard D (June 1986). "Ions binding to S100 proteins. I. Calcium- and zinc-binding properties of bovine brain S100 alpha alpha, S100a (alpha beta), and S100b (beta beta) protein: Zn2+ regulates Ca2+ binding on S100b protein". The Journal of Biological Chemistry. 261 (18): 8192–8203. doi: 10.1016/S0021-9258(19)83895-4 . PMID   3722149.
• Kato K, Kimura S (October 1985). "S100ao (alpha alpha) protein is mainly located in the heart and striated muscles". Biochimica et Biophysica Acta (BBA) - General Subjects. 842 (2–3): 146–150. doi:10.1016/0304-4165(85)90196-5. PMID   4052452.
• Schäfer BW, Wicki R, Engelkamp D, Mattei MG, Heizmann CW (February 1995). "Isolation of a YAC clone covering a cluster of nine S100 genes on human chromosome 1q21: rationale for a new nomenclature of the S100 calcium-binding protein family". Genomics. 25 (3): 638–643. doi:10.1016/0888-7543(95)80005-7. PMID   7759097.
• Engelkamp D, Schäfer BW, Mattei MG, Erne P, Heizmann CW (July 1993). "Six S100 genes are clustered on human chromosome 1q21: identification of two genes coding for the two previously unreported calcium-binding proteins S100D and S100E". Proceedings of the National Academy of Sciences of the United States of America. 90 (14): 6547–6551. Bibcode:1993PNAS...90.6547E. doi: 10.1073/pnas.90.14.6547 . PMC   46969 . PMID   8341667.
• Garbuglia M, Verzini M, Giambanco I, Spreca A, Donato R (February 1996). "Effects of calcium-binding proteins (S-100a(o), S-100a, S-100b) on desmin assembly in vitro". FASEB Journal. 10 (2): 317–324. doi: 10.1096/fasebj.10.2.8641565 . PMID   8641565. S2CID   9718288.
• Landar A, Caddell G, Chessher J, Zimmer DB (September 1996). "Identification of an S100A1/S100B target protein: phosphoglucomutase". Cell Calcium. 20 (3): 279–285. doi:10.1016/S0143-4160(96)90033-0. PMID   8894274.
• Remppis A, Greten T, Schäfer BW, Hunziker P, Erne P, Katus HA, et al. (October 1996). "Altered expression of the Ca(2+)-binding protein S100A1 in human cardiomyopathy". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1313 (3): 253–257. doi: 10.1016/0167-4889(96)00097-3 . PMID   8898862.
• Treves S, Scutari E, Robert M, Groh S, Ottolia M, Prestipino G, et al. (September 1997). "Interaction of S100A1 with the Ca2+ release channel (ryanodine receptor) of skeletal muscle". Biochemistry. 36 (38): 11496–11503. doi:10.1021/bi970160w. PMID   9298970.
• Groves P, Finn BE, Kuźnicki J, Forsén S (January 1998). "A model for target protein binding to calcium-activated S100 dimers". FEBS Letters. 421 (3): 175–179. Bibcode:1998FEBSL.421..175G. doi:10.1016/S0014-5793(97)01535-4. PMID   9468301. S2CID   7749285.
• Mandinova A, Atar D, Schäfer BW, Spiess M, Aebi U, Heizmann CW (July 1998). "Distinct subcellular localization of calcium binding S100 proteins in human smooth muscle cells and their relocation in response to rises in intracellular calcium". Journal of Cell Science. 111 ( Pt 14) (14): 2043–2054. doi:10.1242/jcs.111.14.2043. PMID   9645951.
• Osterloh D, Ivanenkov VV, Gerke V (August 1998). "Hydrophobic residues in the C-terminal region of S100A1 are essential for target protein binding but not for dimerization". Cell Calcium. 24 (2): 137–151. doi:10.1016/S0143-4160(98)90081-1. PMID   9803314.
• Garbuglia M, Verzini M, Donato R (September 1998). "Annexin VI binds S100A1 and S100B and blocks the ability of S100A1 and S100B to inhibit desmin and GFAP assemblies into intermediate filaments". Cell Calcium. 24 (3): 177–191. doi:10.1016/S0143-4160(98)90127-0. PMID   9883272.
• Ridinger K, Ilg EC, Niggli FK, Heizmann CW, Schäfer BW (December 1998). "Clustered organization of S100 genes in human and mouse". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1448 (2): 254–263. doi: 10.1016/S0167-4889(98)00137-2 . PMID   9920416.

External links

• Overview of all the structural information available in the PDB for UniProt : P23297 (Protein S100-A1) at the PDBe-KB .