S100A5

Summary

S100A5 (S100 calcium binding protein A5, HGNC:10495) is a protein-coding gene on chromosome 1q21.3, encoding Protein S100-A5 (P33763). Binds calcium, zinc and copper.

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 a Ca2+ affinity 20- to 100-fold higher than the other S100 proteins studied under identical conditions. This protein also binds Zn2+ and Cu2+, and Cu2+ strongly which impairs the binding of Ca2+. This protein is expressed in very restricted regions of the adult brain.

Source: NCBI Gene 6276 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 15 total
• Druggable target: yes
• MANE Select transcript: NM_001394232

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10495
Approved symbol	S100A5
Name	S100 calcium binding protein A5
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000196420
Ensembl biotype	protein_coding
OMIM	176991
Entrez	6276

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000368717, ENST00000368718, ENST00000963779

RefSeq mRNA: 4 — MANE Select: NM_001394232 NM_001394232, NM_001394233, NM_001394234, NM_002962

CCDS: CCDS1041

Canonical transcript exons

ENST00000368717 — 3 exons

Exon	Start	End
ENSE00001409089	153537147	153537436
ENSE00001447835	153540621	153540934
ENSE00003693679	153540054	153540205

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 72.95.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1710 / max 11.8683, expressed in 78 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14639	0.1710	78

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	72.95	gold quality
endometrium epithelium	UBERON:0004811	72.94	gold quality
parotid gland	UBERON:0001831	72.78	gold quality
left lobe of thyroid gland	UBERON:0001120	71.31	gold quality
right lobe of thyroid gland	UBERON:0001119	70.49	gold quality
thyroid gland	UBERON:0002046	69.90	gold quality
metanephros cortex	UBERON:0010533	68.70	gold quality
leukocyte	CL:0000738	68.18	gold quality
monocyte	CL:0000576	67.82	gold quality
vena cava	UBERON:0004087	67.51	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	65.41	gold quality
mucosa of stomach	UBERON:0001199	64.46	gold quality
paraflocculus	UBERON:0005351	63.66	gold quality
blood	UBERON:0000178	63.56	gold quality
frontal pole	UBERON:0002795	63.02	gold quality
middle frontal gyrus	UBERON:0002702	62.93	gold quality
descending thoracic aorta	UBERON:0002345	62.63	gold quality
left uterine tube	UBERON:0001303	61.29	gold quality
trabecular bone tissue	UBERON:0002483	60.87	gold quality
nasal cavity mucosa	UBERON:0001826	60.46	gold quality
metanephros	UBERON:0000081	59.77	gold quality
skin of leg	UBERON:0001511	59.74	gold quality
myocardium	UBERON:0002349	59.62	gold quality
rectum	UBERON:0001052	59.29	gold quality
lower esophagus mucosa	UBERON:0035834	58.98	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	58.70	gold quality
thoracic aorta	UBERON:0001515	58.62	gold quality
skin of abdomen	UBERON:0001416	58.43	gold quality
ascending aorta	UBERON:0001496	58.38	gold quality
superficial temporal artery	UBERON:0001614	58.32	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.07

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting S100A5, 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-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-6515-5P	97.08	65.48	1219
HSA-MIR-3192-5P	96.98	65.76	1926

Literature-anchored findings (GeneRIF, showing 6)

• Strongly expressed at 12 weeks gestation in the cells and fibers of the hippocampus, and then decreased with age. In the temporal cortex, detected from 12 weeks onwards, peaked at 20 to 24 weeks, and then decreased with age. (PMID:12645008)
• Homodimeric solution structures of S100A5 in both apo & Ca(II)-loaded forms were obtained & show conformational rearrangement on Ca binding. Also, large mobility was observed in hinge loop of apo-S100A5; this mobility was not quenched in Ca form. (PMID:19536568)
• These results indicated that pentamidine blocks the binding between S100A5 and RAGE V domain. This finding is useful for the development of new anti-proliferation drugs. (PMID:27297108)
• S100A5 employs the periphery of the dimer interface to interact with RAGE-v (PMID:28017722)
• Isothermal titration calorimetry measured the binding of peptides with diverse sequence and biochemistry to human S100A5 and S110A6. These proteins bound distinct, but overlapping, sets of peptide targets. A single historical mutation, when reverted in human S100A5, gave it the ability to bind an S100A6-specific peptide. The specificity of S100 peptide interfaces is likely important for the biology of these proteins. (PMID:29240404)
• Were Ancestral Proteins Less Specific? (PMID:33528559)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	s100s	ENSDARG00000036773
danio_rerio	s100a10a	ENSDARG00000037425
danio_rerio	s100t	ENSDARG00000055589
mus_musculus	S100a5	ENSMUSG00000001023
rattus_norvegicus	S100a5	ENSRNOG00000011748

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), S100A3 (ENSG00000188015), S100A16 (ENSG00000188643), SNTN (ENSG00000188817), S100A13 (ENSG00000189171), S100A14 (ENSG00000189334), S100A4 (ENSG00000196154), S100A2 (ENSG00000196754), S100A10 (ENSG00000197747), S100A6 (ENSG00000197956)

Protein

Protein identifiers

Protein S100-A5 — P33763 (reviewed: P33763)

Alternative names: Protein S-100D, S100 calcium-binding protein A5

All UniProt accessions (1): P33763

UniProt curated annotations — full annotation on UniProt →

Function. Binds calcium, zinc and copper. One subunit can simultaneously bind 2 calcium ions or 2 copper ions plus 1 zinc ion. Calcium and copper ions compete for the same binding sites.

Subunit / interactions. Homodimer.

Similarity. Belongs to the S-100 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P33763-1	1	yes
P33763-2	2

RefSeq proteins (4): NP_001381161, NP_001381162, NP_001381163, NP_002953 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001751	S100/CaBP7/8-like_CS	Conserved_site
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013787	S100_Ca-bd_sub	Domain
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR034325	S-100_dom	Domain

Pfam: PF01023

UniProt features (21 total): binding site 7, helix 4, strand 3, domain 2, turn 2, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6WN7	X-RAY DIFFRACTION	1.25
4DIR	X-RAY DIFFRACTION	2.6
2KAX	SOLUTION NMR
2KAY	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P33763-F1	94.04	0.87

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 (7): 28; 33; 60; 62; 64; 66; 71

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 125 (showing top): MODULE_255, LFA1_Q6, MORF_BRCA1, MODULE_317, TGACCTY_ERR1_Q2, MORF_RAD51L3, TGANTCA_AP1_C, YAMASHITA_METHYLATED_IN_PROSTATE_CANCER, MORF_ATF2, MORF_BCL2L11, MORF_PPP2R5B, SAFFORD_T_LYMPHOCYTE_ANERGY, MODULE_112, AP1FJ_Q2, chr1q21

GO Biological Process (0):

GO Molecular Function (9): copper ion binding (GO:0005507), calcium ion binding (GO:0005509), zinc ion binding (GO:0008270), protein homodimerization activity (GO:0042803), calcium-dependent protein binding (GO:0048306), protein binding (GO:0005515), identical protein binding (GO:0042802), metal ion binding (GO:0046872), transition metal ion binding (GO:0046914)

GO Cellular Component (2): nucleus (GO:0005634), neuronal cell body (GO:0043025)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transition metal ion binding	2
metal ion binding	2
protein binding	2
identical protein binding	1
protein dimerization activity	1
calcium ion binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
somatodendritic compartment	1
cell body	1

Protein interactions and networks

STRING

458 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
S100A5	S100A16	Q96FQ6	762
S100A5	HRNR	Q86YZ3	732
S100A5	S100A7	P31151	609
S100A5	S100A14	Q9HCY8	582
S100A5	S100G	P29377	577
S100A5	S100A7A	Q86SG5	575
S100A5	S100A7L2	Q5SY68	541
S100A5	AGER	Q15109	529
S100A5	GINM1	Q9NU53	522
S100A5	S100A1	P23297	512
S100A5	MFSD6L	Q8IWD5	469
S100A5	ST6GALNAC1	Q9NSC7	467
S100A5	ARMCX4	Q5H9R4	456
S100A5	S100A3	P33764	441
S100A5	CACHD1	Q5VU97	435

IntAct

21 interactions, top by confidence:

A	B	Type	Score
TP53	TP53	psi-mi:“MI:0915”(physical association)	0.980
S100A5	CACYBP	psi-mi:“MI:0407”(direct interaction)	0.610
CACYBP	S100A5	psi-mi:“MI:0915”(physical association)	0.610
TRPM4	S100A5	psi-mi:“MI:0407”(direct interaction)	0.610
S100A5	TRPM4	psi-mi:“MI:0915”(physical association)	0.610
S100A5	TP53	psi-mi:“MI:0407”(direct interaction)	0.540
S100A5	MYH9	psi-mi:“MI:0407”(direct interaction)	0.540
MYH9	S100A5	psi-mi:“MI:0915”(physical association)	0.540
S100A5	CAPZA1	psi-mi:“MI:0407”(direct interaction)	0.540
CAPZA1	S100A5	psi-mi:“MI:0915”(physical association)	0.540
S100A5	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.540
S100A5	MDM4	psi-mi:“MI:0407”(direct interaction)	0.540
S100A5	AREG	psi-mi:“MI:0407”(direct interaction)	0.440
SLC8A1	SLC8A1	psi-mi:“MI:0915”(physical association)	0.400
CEP20	S100A5	psi-mi:“MI:0915”(physical association)	0.400
MDM4	MDM4	psi-mi:“MI:0915”(physical association)	0.400
CEP43	CEP43	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF6B	ORC4	psi-mi:“MI:0914”(association)	0.350

BioGRID (2): S100A5 (Affinity Capture-MS), S100A5 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A5PJN0, A7K6Y8, A7K6Y9, F1SSF9, O73763, O76038, O77791, P05109, P06702, P27005, P28318, P28782, P31725, P33763, P43367, P45961, P50115, P50116, P50117, P63083, P63084, P79105, P80511, Q01449, Q06A97, Q0VFG3, Q14ST5, Q28050, Q3MHP3, Q4R6C5, Q5E9G1, Q5SY68, Q5XJX1, Q63ZJ3, Q6AXZ3, Q6DJ05, Q6R556, Q6S5I3, Q75KU4, Q803V3

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.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

425 predictions. Top by Δscore:

Variant	Effect	Δscore
1:153537440:T:C	acceptor_gain	1.0000
1:153537440:T:TC	acceptor_gain	1.0000
1:153537449:C:CT	acceptor_gain	1.0000
1:153540206:C:CC	acceptor_gain	1.0000
1:153537434:CATCT:C	acceptor_gain	0.9900
1:153537438:T:C	acceptor_gain	0.9900
1:153537449:C:T	acceptor_gain	0.9900
1:153537450:A:T	acceptor_gain	0.9900
1:153538237:G:A	donor_gain	0.9900
1:153540049:CCTA:C	donor_loss	0.9900
1:153540050:CTAC:C	donor_loss	0.9900
1:153540051:TA:T	donor_loss	0.9900
1:153540052:ACCT:A	donor_gain	0.9900
1:153540052:ACCTC:A	donor_gain	0.9900
1:153540053:CCTC:C	donor_gain	0.9900
1:153540053:CCTCC:C	donor_gain	0.9900
1:153540201:CAGCT:C	acceptor_gain	0.9900
1:153540202:AGCT:A	acceptor_gain	0.9900
1:153540202:AGCTC:A	acceptor_loss	0.9900
1:153540203:GCT:G	acceptor_gain	0.9900
1:153540204:CT:C	acceptor_gain	0.9900
1:153540204:CTCTG:C	acceptor_gain	0.9900
1:153540205:TC:T	acceptor_loss	0.9900
1:153540205:TCT:T	acceptor_gain	0.9900
1:153540206:C:G	acceptor_gain	0.9900
1:153540206:CTGT:C	acceptor_loss	0.9900
1:153540207:T:G	acceptor_loss	0.9900
1:153537434:CAT:C	acceptor_gain	0.9800
1:153537435:ATCT:A	acceptor_loss	0.9800
1:153537436:TCT:T	acceptor_loss	0.9800

AlphaMissense

623 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:153540144:A:C	F16L	0.995
1:153540144:A:T	F16L	0.995
1:153540146:A:G	F16L	0.995
1:153540082:A:G	L37P	0.983
1:153540091:A:G	L34P	0.982
1:153537368:G:C	F69L	0.981
1:153537368:G:T	F69L	0.981
1:153537370:A:G	F69L	0.981
1:153537337:A:G	C80R	0.975
1:153537361:A:G	Y72H	0.973
1:153540106:A:T	L29Q	0.973
1:153540145:A:G	F16S	0.973
1:153540170:C:G	A8P	0.966
1:153537360:T:G	Y72S	0.965
1:153537369:A:G	F69S	0.964
1:153537335:G:C	C80W	0.963
1:153537395:G:C	D60E	0.957
1:153537395:G:T	D60E	0.957
1:153540166:A:G	L9P	0.957
1:153537383:G:C	D64E	0.956
1:153537383:G:T	D64E	0.956
1:153537389:G:C	N62K	0.954
1:153537389:G:T	N62K	0.954
1:153540106:A:G	L29P	0.954
1:153537371:G:C	D68E	0.952
1:153537371:G:T	D68E	0.952
1:153537396:T:G	D60A	0.952
1:153537361:A:C	Y72D	0.951
1:153540134:A:G	S20P	0.949
1:153537363:T:A	E71V	0.948

dbSNP variants (sampled 300 via entrez): RS1000286018 (1:153540503 G>A), RS1001411945 (1:153540886 G>A,T), RS1002875101 (1:153542905 A>C), RS1003085771 (1:153539607 A>G), RS1003199194 (1:153537725 A>C), RS1003279539 (1:153538641 A>T), RS1003571555 (1:153544167 C>T), RS1004098143 (1:153543323 A>G), RS1005090577 (1:153536920 C>T), RS1005115519 (1:153543086 C>A,T), RS1005364699 (1:153537204 G>A), RS1005589368 (1:153541611 G>A,T), RS1005770068 (1:153544656 C>G,T), RS1005961597 (1:153544307 T>C), RS1006947044 (1:153545105 A>G)

Disease associations

OMIM: gene MIM:176991 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000461_18	Hippocampal atrophy	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005039	hippocampal atrophy

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296264 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Fulvestrant	affects cotreatment, decreases methylation, decreases reaction, increases expression	2
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	affects cotreatment, decreases methylation	1
beta-lapachone	increases expression	1
arsenite	decreases reaction, increases expression, decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
clothianidin	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Decitabine	increases expression	1
Arsenic	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases expression	1
Estradiol	decreases expression, decreases reaction, increases expression	1
Sodium Dodecyl Sulfate	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
Zinc	decreases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6079551	Binding	Inhibition of S100A5 (unknown origin) by Alphascreen assay	Covalent Inhibitors of S100A4 Block the Formation of a Pro-Metastasis Non-Muscle Myosin 2A Complex. — J Med Chem

Clinical trials (associated diseases)

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