S100A3

Summary

S100A3 (S100 calcium binding protein A3, HGNC:10493) is a protein-coding gene on chromosome 1q21.3, encoding Protein S100-A3 (P33764). Binds both calcium and zinc.

The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. 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 has the highest content of cysteines of all S100 proteins, has a high affinity for Zinc, and is highly expressed in human hair cuticle. The precise function of this protein is unknown.

Source: NCBI Gene 6274 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 2 total
• MANE Select transcript: NM_002960

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10493
Approved symbol	S100A3
Name	S100 calcium binding protein A3
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000188015
Ensembl biotype	protein_coding
OMIM	176992
Entrez	6274

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000368712, ENST00000368713, ENST00000873876, ENST00000873877, ENST00000929796, ENST00000969280

RefSeq mRNA: 1 — MANE Select: NM_002960 NM_002960

CCDS: CCDS1043

Canonical transcript exons

ENST00000368713 — 3 exons

Exon	Start	End
ENSE00001424757	153547329	153547846
ENSE00001447827	153548345	153548490
ENSE00001447828	153549181	153549258

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 92.57.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9707 / max 55.6107, expressed in 751 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14652	1.4224	612
14651	0.2854	164
14650	0.1630	77
14649	0.0999	49

Top tissues by expression

286 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	92.57	gold quality
upper arm skin	UBERON:0004263	86.41	gold quality
esophagus mucosa	UBERON:0002469	86.31	gold quality
skin of leg	UBERON:0001511	83.10	gold quality
skin of abdomen	UBERON:0001416	82.23	gold quality
ectocervix	UBERON:0012249	81.31	gold quality
zone of skin	UBERON:0000014	81.18	gold quality
upper lobe of left lung	UBERON:0008952	81.01	gold quality
endocervix	UBERON:0000458	80.60	gold quality
right coronary artery	UBERON:0001625	79.75	gold quality
vagina	UBERON:0000996	79.26	gold quality
upper lobe of lung	UBERON:0008948	78.66	gold quality
decidua	UBERON:0002450	78.21	gold quality
esophagus	UBERON:0001043	77.97	gold quality
descending thoracic aorta	UBERON:0002345	77.69	gold quality
tongue squamous epithelium	UBERON:0006919	77.67	gold quality
cartilage tissue	UBERON:0002418	77.65	gold quality
left coronary artery	UBERON:0001626	77.52	gold quality
stromal cell of endometrium	CL:0002255	77.04	gold quality
thoracic aorta	UBERON:0001515	77.01	gold quality
ascending aorta	UBERON:0001496	76.87	gold quality
apex of heart	UBERON:0002098	76.53	gold quality
coronary artery	UBERON:0001621	76.02	gold quality
aorta	UBERON:0000947	75.86	gold quality
tibial artery	UBERON:0007610	75.33	gold quality
popliteal artery	UBERON:0002250	75.32	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	74.91	gold quality
metanephros cortex	UBERON:0010533	74.67	gold quality
hair follicle	UBERON:0002073	74.27	gold quality
left uterine tube	UBERON:0001303	74.03	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	42.91
E-ANND-3	yes	5.27

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFATC2

miRNA regulators (miRDB)

19 targeting S100A3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4506	99.34	67.47	526
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-198	98.70	67.32	920
HSA-MIR-4266	98.53	67.29	1035
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-5681A	97.99	67.17	1658
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-3936	97.64	64.47	732
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-6791-3P	97.45	64.31	1123
HSA-MIR-6829-3P	97.45	64.31	1137
HSA-MIR-612	97.26	65.95	1597
HSA-MIR-6860	97.21	66.31	1656
HSA-MIR-6820-5P	94.04	61.13	161

Literature-anchored findings (GeneRIF, showing 9)

• crystal structure of S100A3 at 1.7-A resolution (PMID:12045193)
• structure was solved by MIRAS phasing (PMID:12136135)
• Purification and characterization of the S100A3 protein from human hair cuticles. (PMID:12470658)
• cytoplasmic S100A3 within the cuticular layer is mostly co-localized with the type III isoform of peptidylarginine deiminase (PAD3) (PMID:18083705)
• One disulfide bridge is between Cys30 in the N-terminal pseudo-EF-hand and Cys68 in the C-terminal EF-hand (SS1), and another disulfide bridge attaches Cys99 in the C-terminal coil structure to Cys81 in helix IV (SS2). (PMID:21377473)
• S100A3 expression is significantly upregulated in human masticatory mucosa during wound healing (PMID:28005267)
• Opposite effects on RARalpha/PML-RARalpha levels and ATRA-induced differentiation are observed upon S100A3 overexpression. (PMID:30532072)
• This review discusses the role and potential use as biomarkers of semaphorin 3A (SEMA3A), protocadherin 9 (PCDH9), and S100 calcium binding protein A3 (S100A3) in carcinogenesis and chemoresistance of various tumors, including ovarian cancer. (PMID:31059116)
• An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes S100A3 and S100A13. (PMID:31073086)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	s100s	ENSDARG00000036773
danio_rerio	s100a10a	ENSDARG00000037425
danio_rerio	s100t	ENSDARG00000055589
mus_musculus	S100a3	ENSMUSG00000001021
rattus_norvegicus	S100a3	ENSRNOG00000012008

Paralogs (21): CRNN (ENSG00000143536), S100A8 (ENSG00000143546), S100A7 (ENSG00000143556), S100B (ENSG00000160307), S100A1 (ENSG00000160678), S100A11 (ENSG00000163191), S100A9 (ENSG00000163220), S100A12 (ENSG00000163221), S100P (ENSG00000163993), S100G (ENSG00000169906), S100Z (ENSG00000171643), S100A7A (ENSG00000184330), S100A16 (ENSG00000188643), SNTN (ENSG00000188817), S100A13 (ENSG00000189171), S100A14 (ENSG00000189334), S100A4 (ENSG00000196154), S100A5 (ENSG00000196420), S100A2 (ENSG00000196754), S100A10 (ENSG00000197747), S100A6 (ENSG00000197956)

Protein

Protein identifiers

Protein S100-A3 — P33764 (reviewed: P33764)

Alternative names: Protein S-100E, S100 calcium-binding protein A3

All UniProt accessions (1): P33764

UniProt curated annotations — full annotation on UniProt →

Function. Binds both calcium and zinc. May be involved in calcium-dependent cuticle cell differentiation, hair shaft and hair cuticular barrier formation.

Subunit / interactions. Homodimer and homotetramer for the citrullinated form.

Subcellular location. Cytoplasm.

Tissue specificity. Skin specific, specifically expressed at the inner endocuticle of hair fibers.

Post-translational modifications. More than half of the arginine residues undergo citrullination by PAD1 and PAD2. Arg-51 is specifically citrullinated by PAD3 and promotes tetramerization.

Similarity. Belongs to the S-100 family.

RefSeq proteins (1): NP_002951* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001751	S100/CaBP7/8-like_CS	Conserved_site
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013787	S100_Ca-bd_sub	Domain
IPR034325	S-100_dom	Domain

Pfam: PF01023

UniProt features (35 total): binding site 11, helix 5, mutagenesis site 4, strand 3, turn 3, modified residue 2, disulfide bond 2, domain 2, initiator methionine 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3NSO	X-RAY DIFFRACTION	1.45
3NSL	X-RAY DIFFRACTION	1.5
3NSK	X-RAY DIFFRACTION	1.55
1KSO	X-RAY DIFFRACTION	1.7
3NSI	X-RAY DIFFRACTION	2.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P33764-F1	81.60	0.35

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (11): 74; 83; 86; 87; 93; 28; 33; 63; 65; 67; 69

Post-translational modifications (2): 2, 51

Disulfide bonds (2): 30–68, 81–99

Mutagenesis-validated functional residues (4):

Position	Phenotype
30	abolishes calcium binding; when associated with ala-68.
68	abolishes calcium binding; when associated with ala-30.
81	increases affinity for calcium; when associated with ala-99.
99	increases affinity for calcium; when associated with ala-81.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 92 (showing top): RNGTGGGC_UNKNOWN, BROWNE_HCMV_INFECTION_6HR_DN, PEREZ_TP63_TARGETS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, HUMMERICH_BENIGN_SKIN_TUMOR_DN, CAGCTG_AP4_Q5, MODULE_70, GERY_CEBP_TARGETS, KIM_RESPONSE_TO_TSA_AND_DECITABINE_UP, MARTINEZ_RB1_TARGETS_DN, BROWNE_HCMV_INFECTION_14HR_DN, BASAKI_YBX1_TARGETS_UP, MARKEY_RB1_ACUTE_LOF_UP, HAMAI_APOPTOSIS_VIA_TRAIL_DN

GO Biological Process (0):

GO Molecular Function (5): calcium ion binding (GO:0005509), transition metal ion binding (GO:0046914), calcium-dependent protein binding (GO:0048306), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metal ion binding	2
cytoplasm	2
cellular anatomical structure	2
calcium ion binding	1
protein binding	1
binding	1
cation binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1065 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
S100A3	S100A16	Q96FQ6	785
S100A3	HRNR	Q86YZ3	762
S100A3	PADI3	Q9ULW8	705
S100A3	S100A13	Q99584	700
S100A3	TCHHL1	Q5QJ38	626
S100A3	S100A7	P31151	605
S100A3	S100A14	Q9HCY8	591
S100A3	S100A10	P08206	584
S100A3	S100G	P29377	543
S100A3	S100A7A	Q86SG5	517
S100A3	S100A7L2	Q5SY68	513
S100A3	KPRP	Q5T749	478
S100A3	KRTAP3-3	Q9BYR6	473
S100A3	KRT73	Q86Y46	459
S100A3	KRTAP17-1	Q9BYP8	458

IntAct

82 interactions, top by confidence:

A	B	Type	Score
TP53	TP53	psi-mi:“MI:0915”(physical association)	0.980
ANXA9	PPL	psi-mi:“MI:0914”(association)	0.660
RAB11B	SH3BP5	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
S100A2	S100A3	psi-mi:“MI:0915”(physical association)	0.630
S100A3	S100Z	psi-mi:“MI:0915”(physical association)	0.560
S100A3	LNX1	psi-mi:“MI:0915”(physical association)	0.560
S100A3	S100A10	psi-mi:“MI:0915”(physical association)	0.560
S100A1	S100A3	psi-mi:“MI:0915”(physical association)	0.560
TRPM4	S100A3	psi-mi:“MI:0407”(direct interaction)	0.540
S100A3	TRPM4	psi-mi:“MI:0915”(physical association)	0.540
MRPL38	DUSP14	psi-mi:“MI:0914”(association)	0.530
OR51E2	DUSP14	psi-mi:“MI:0914”(association)	0.530
FBXL4	DUSP14	psi-mi:“MI:0914”(association)	0.530
SEMG2	VSIG8	psi-mi:“MI:0914”(association)	0.530
TFG	CRYAB	psi-mi:“MI:0914”(association)	0.530
SKA2	VSIG8	psi-mi:“MI:0914”(association)	0.530
S100A3	MYH9	psi-mi:“MI:0407”(direct interaction)	0.440
S100A3	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A3	TP53	psi-mi:“MI:0915”(physical association)	0.400
CEP20	S100A3	psi-mi:“MI:0915”(physical association)	0.400
CEP43	CEP43	psi-mi:“MI:0915”(physical association)	0.400
TFG	HNRNPCL1	psi-mi:“MI:0914”(association)	0.350
RAB11FIP4	RAB11FIP3	psi-mi:“MI:0914”(association)	0.350

BioGRID (80): S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS)

ESM2 similar proteins: A0JN27, A5PJI5, G3MWR8, G3V9T7, O43681, O54984, O94925, P04163, P05943, P08207, P22234, P27003, P30626, P33764, P51583, P60902, P60903, P62504, P62818, P62819, Q13888, Q15303, Q2TBV5, Q2YDM2, Q3MHC2, Q5HZM6, Q5NVE6, Q5R4U9, Q5RB59, Q5RIC0, Q5TA45, Q5TDH0, Q5ZHS1, Q5ZIH0, Q61527, Q62956, Q64119, Q6NVL5, Q6P1K8, Q6PH85

Diamond homologs: A7K6Y9, O77691, O77791, P02632, P02633, P02634, P02638, P02639, P04271, P04631, P05942, P05964, P06702, P06703, P07091, P10462, P14069, P20930, P23297, P24480, P25815, P26447, P27003, P28318, P28783, P29034, P29377, P30801, P33763, P33764, P35466, P35467, P50114, P50116, P50117, P56565, P62818, P62819, P63083, P63084

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	5	45.8×	3e-05
Diseases of signal transduction by growth factor receptors and second messengers	7	8.3×	5e-04
Membrane Trafficking	9	7.0×	2e-04
Vesicle-mediated transport	9	6.5×	3e-04
Adaptive Immune System	7	4.3×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

2 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

550 predictions. Top by Δscore:

Variant	Effect	Δscore
1:153547843:CAGT:C	acceptor_gain	1.0000
1:153547845:GT:G	acceptor_gain	1.0000
1:153547846:TC:T	acceptor_loss	1.0000
1:153547847:C:CC	acceptor_gain	1.0000
1:153547849:G:C	acceptor_gain	1.0000
1:153547849:G:GC	acceptor_gain	1.0000
1:153547852:C:CT	acceptor_gain	1.0000
1:153547853:A:T	acceptor_gain	1.0000
1:153547863:T:TC	acceptor_gain	1.0000
1:153548339:GCTCA:G	donor_loss	1.0000
1:153548340:CTCA:C	donor_loss	1.0000
1:153548341:TCAC:T	donor_loss	1.0000
1:153548342:CAC:C	donor_loss	1.0000
1:153548343:A:AC	donor_gain	1.0000
1:153548344:C:CC	donor_gain	1.0000
1:153548491:C:CC	acceptor_gain	1.0000
1:153547842:TCAGT:T	acceptor_gain	0.9900
1:153547843:CAGTC:C	acceptor_gain	0.9900
1:153547844:AGT:A	acceptor_gain	0.9900
1:153547862:G:C	acceptor_gain	0.9900
1:153547863:T:C	acceptor_gain	0.9900
1:153548344:CCG:C	donor_gain	0.9900
1:153548486:CCTCA:C	acceptor_gain	0.9900
1:153548487:CTCA:C	acceptor_gain	0.9900
1:153548487:CTCAC:C	acceptor_gain	0.9900
1:153548488:TCACT:T	acceptor_gain	0.9900
1:153548489:CA:C	acceptor_gain	0.9900
1:153548343:AC:A	donor_gain	0.9800
1:153548344:CC:C	donor_gain	0.9800
1:153548344:CCGG:C	donor_gain	0.9800

AlphaMissense

659 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:153548438:G:C	F16L	0.981
1:153548438:G:T	F16L	0.981
1:153548440:A:G	F16L	0.981
1:153547741:A:G	C83R	0.947
1:153547772:A:C	F72L	0.942
1:153547772:A:T	F72L	0.942
1:153547774:A:G	F72L	0.942
1:153548385:A:G	L34P	0.920
1:153548400:A:T	L29H	0.918
1:153548439:A:G	F16S	0.910
1:153547739:A:C	C83W	0.897
1:153547773:A:G	F72S	0.890
1:153547718:G:C	F90L	0.881
1:153547718:G:T	F90L	0.881
1:153547720:A:G	F90L	0.881
1:153548439:A:C	F16C	0.881
1:153548376:A:G	L37P	0.880
1:153547765:A:G	Y75H	0.879
1:153547773:A:C	F72C	0.873
1:153547765:A:C	Y75D	0.871
1:153547767:T:A	E74V	0.869
1:153547764:T:G	Y75S	0.866
1:153547787:G:C	D67E	0.866
1:153547787:G:T	D67E	0.866
1:153547779:A:T	V70E	0.860
1:153547799:G:C	D63E	0.859
1:153547799:G:T	D63E	0.859
1:153548440:A:T	F16I	0.858
1:153547815:A:G	F58S	0.850
1:153547752:A:G	L79P	0.846

dbSNP variants (sampled 300 via entrez): RS1001097220 (1:153548255 C>T), RS1001565381 (1:153546837 C>A,G,T), RS1001827765 (1:153547068 C>A,T), RS1001928447 (1:153550981 G>A), RS1003175956 (1:153548620 G>A), RS1003730769 (1:153549421 C>A,T), RS1003909087 (1:153549168 G>A), RS1003931790 (1:153548557 T>A,C), RS1004004567 (1:153549608 G>A), RS1004344518 (1:153548920 G>C), RS1005436 (1:153549456 G>A,C), RS1005586111 (1:153550445 C>T), RS1005614265 (1:153550165 G>A), RS1005646928 (1:153549944 C>G), RS1005743756 (1:153547149 T>C)

Disease associations

OMIM: gene MIM:176992 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	5
Decitabine	affects methylation, affects cotreatment, increases expression	3
Valproic Acid	decreases expression, increases expression, affects expression	3
sodium arsenite	increases expression, decreases expression	2
Silicon Dioxide	increases expression	2
Aflatoxin B1	increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
trichostatin A	affects cotreatment, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
maleic acid	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
obeticholic acid	decreases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	increases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	decreases expression	1
Air Pollutants	increases expression	1
Calcitriol	increases expression	1
Diethylhexyl Phthalate	increases expression	1
Diethylnitrosamine	increases expression	1
Fluorouracil	decreases expression, affects response to substance	1
Ivermectin	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.