ASTL

Summary

ASTL (astacin like metalloendopeptidase, HGNC:31704) is a protein-coding gene on chromosome 2q11.2, encoding Astacin-like metalloendopeptidase (Q6HA08). Oocyte-specific oolemmal receptor involved in sperm and egg adhesion and fertilization.

Predicted to enable aspartic-type peptidase activity; glutamic-type peptidase activity; and metalloendopeptidase activity. Predicted to be involved in several processes, including negative regulation of binding activity of sperm to zona pellucida; positive regulation of protein processing; and prevention of polyspermy. Predicted to be located in cortical granule and plasma membrane.

Source: NCBI Gene 431705 — RefSeq curated summary.

At a glance

• Gene–disease (curated): oocyte maturation defect 11 (Limited, GenCC)
• Clinical variants (ClinVar): 95 total — 1 pathogenic
• Phenotypes (HPO): 3
• MANE Select transcript: NM_001002036

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31704
Approved symbol	ASTL
Name	astacin like metalloendopeptidase
Location	2q11.2
Locus type	gene with protein product
Status	Approved
Aliases	ovastacin, SAS1B
Ensembl gene	ENSG00000188886
Ensembl biotype	protein_coding
OMIM	608860
Entrez	431705

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000342380, ENST00000470582, ENST00000867255

RefSeq mRNA: 1 — MANE Select: NM_001002036 NM_001002036

CCDS: CCDS33249

Canonical transcript exons

ENST00000342380 — 9 exons

Exon	Start	End
ENSE00001364407	96129824	96129978
ENSE00001366112	96130064	96130145
ENSE00001369654	96122818	96124271
ENSE00001374492	96133965	96134058
ENSE00001382523	96133425	96133542
ENSE00001384861	96137575	96137700
ENSE00001391218	96132540	96132721
ENSE00001404132	96138382	96138502
ENSE00003563298	96135351	96135412

Expression profiles

Bgee: expression breadth ubiquitous, 101 present calls, max score 72.76.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow	UBERON:0002371	72.76	gold quality
bone marrow cell	CL:0002092	72.32	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	62.50	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	61.94	gold quality
blood	UBERON:0000178	59.38	gold quality
skin of abdomen	UBERON:0001416	59.24	gold quality
granulocyte	CL:0000094	58.49	gold quality
zone of skin	UBERON:0000014	58.31	gold quality
skin of leg	UBERON:0001511	57.46	gold quality
spleen	UBERON:0002106	56.06	gold quality
right lung	UBERON:0002167	53.89	gold quality
lymph node	UBERON:0000029	53.32	gold quality
colonic epithelium	UBERON:0000397	52.05	silver quality
lower esophagus mucosa	UBERON:0035834	51.80	gold quality
cerebellar hemisphere	UBERON:0002245	51.29	gold quality
cerebellar cortex	UBERON:0002129	51.28	gold quality
cerebellum	UBERON:0002037	51.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	50.85	gold quality
urinary bladder	UBERON:0001255	50.57	gold quality
vermiform appendix	UBERON:0001154	49.65	gold quality
right frontal lobe	UBERON:0002810	48.93	gold quality
tonsil	UBERON:0002372	48.91	gold quality
small intestine Peyer’s patch	UBERON:0003454	47.79	gold quality
gall bladder	UBERON:0002110	47.68	gold quality
Brodmann (1909) area 9	UBERON:0013540	47.30	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	46.91	gold quality
frontal cortex	UBERON:0001870	46.90	gold quality
small intestine	UBERON:0002108	46.54	gold quality
apex of heart	UBERON:0002098	46.27	gold quality
prefrontal cortex	UBERON:0000451	46.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.31

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 4)

• SAS1B protein [ovastacin] shows temporal and spatial restriction to oocytes in several eutherian orders and initiates translation at the primary to secondary follicle transition. (PMID:24038607)
• The SAS1B metalloproteinase is proposed as a prototype cancer-oocyte tumor surface neoantigen for development of targeted immunotherapeutics with limited on-target/off tumor effects predicted to be restricted to the population of growing oocytes. (PMID:26327203)
• The detection of SAS1B in serum provides clues for early diagnosis of thyroid cancer. (PMID:33629311)
• ASTL is mutated in female infertility. (PMID:34704130)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	hce2l2	ENSDARG00000070011
mus_musculus	Astl	ENSMUSG00000050468
rattus_norvegicus	Astl	ENSRNOG00000022603
drosophila_melanogaster	CG6696	FBGN0030947
drosophila_melanogaster	CG10280	FBGN0037395
drosophila_melanogaster	CG5715	FBGN0039180
caenorhabditis_elegans		WBGENE00003521
caenorhabditis_elegans		WBGENE00003522
caenorhabditis_elegans		WBGENE00021221

Paralogs (35): NRXN3 (ENSG00000021645), TLL1 (ENSG00000038295), CP (ENSG00000047457), DCBLD2 (ENSG00000057019), HEPH (ENSG00000089472), TLL2 (ENSG00000095587), NRP1 (ENSG00000099250), PCOLCE (ENSG00000106333), CNTNAP3 (ENSG00000106714), CUBN (ENSG00000107611), CNTNAP1 (ENSG00000108797), NRXN2 (ENSG00000110076), MEP1A (ENSG00000112818), NRP2 (ENSG00000118257), CUZD1 (ENSG00000138161), MFGE8 (ENSG00000140545), MEP1B (ENSG00000141434), PDGFC (ENSG00000145431), CNTNAP4 (ENSG00000152910), CNTNAP3B (ENSG00000154529), CNTNAP5 (ENSG00000155052), CDCP2 (ENSG00000157211), PCOLCE2 (ENSG00000163710), EDIL3 (ENSG00000164176), NETO1 (ENSG00000166342), BMP1 (ENSG00000168487), PDGFD (ENSG00000170962), NETO2 (ENSG00000171208), CNTNAP2 (ENSG00000174469), NRXN1 (ENSG00000179915), HEPHL1 (ENSG00000181333), F8 (ENSG00000185010), F5 (ENSG00000198734), MFRP (ENSG00000235718), CNTNAP3C (ENSG00000283378)

Protein

Protein identifiers

Astacin-like metalloendopeptidase — Q6HA08 (reviewed: Q6HA08)

Alternative names: Oocyte astacin, Ovastacin, ZP2-proteinase

All UniProt accessions (1): Q6HA08

UniProt curated annotations — full annotation on UniProt →

Function. Oocyte-specific oolemmal receptor involved in sperm and egg adhesion and fertilization. Plays a role in the polyspermy inhibition. Probably acts as a protease for the post-fertilization cleavage of ZP2. Cleaves the sperm-binding ZP2 at the surface of the zona pellucida after fertilization and cortical granule exocytosis, rendering the zona pellucida unable to support further sperm binding.

Subunit / interactions. Interacts (via N-terminal domain) with SPACA3; the interaction occurs during fertilization.

Subcellular location. Cytoplasm. Cell membrane. Cytoplasmic vesicle. Secretory vesicle. Cortical granule.

Disease relevance. Oocyte/zygote/embryo maturation arrest 11 (OZEMA11) [MIM:619643] An autosomal recessive disorder characterized by decreased or absent fertility and poor embryonic outcomes with assisted reproductive technology. The disease may be caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

RefSeq proteins (1): NP_001002036* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001506	Peptidase_M12A	Domain
IPR006026	Peptidase_Metallo	Domain
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily

Pfam: PF01400

Enzyme classification (BRENDA):

• EC 3.4.24.21 — astacin (BRENDA: 25 organisms, 107 substrates, 82 inhibitors, 35 Km, 36 kcat entries)

Substrate kinetics (BRENDA)

37 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DANSYL-GLY-LYS-ASN-ALA-PRO-LEU-VAL	0.4–0.52	2
2-AMINOBENZOYL-ARG-GLY-PRO-PHE-SER-PRO-(4-NITRO)	0.327	1
2-AMINOBENZOYL-ARG-HYP-GLY-PHE-SER-PRO-(4-NITRO)	0.044	1
2-AMINOBENZOYL-ARG-PRO-GLY-ALA-SER-PRO-(4-NITRO)	0.154	1
2-AMINOBENZOYL-ARG-PRO-GLY-GLU-SER-PRO-(4-NITRO)	0.954	1
2-AMINOBENZOYL-ARG-PRO-GLY-LYS-SER-PRO-(4-NITRO)	0.281	1
2-AMINOBENZOYL-ARG-PRO-ILE-PHE-SER-PRO-(4-NITRO)	0.029	1
AC-RE(EDANS)-DRNLEVGDDPYK(DABCYL)-NH2	0.034	1
ARG-PRO-PRO-GLY-(4-NITRO)PHE-ALA-PRO-PHE-ARG	0.306	1
ARG-PRO-PRO-GLY-(4-NITRO)PHE-ARG-PRO-PHE-ARG	0.209	1
ARG-PRO-PRO-GLY-(4-NITRO)PHE-LYS-PRO-PHE-ARG	0.116	1
ARG-PRO-PRO-GLY-(4-NITRO)PHE-PHE-PRO-PHE-ARG	0.194	1
ARG-PRO-PRO-GLY-(4-NITRO)PHE-SER-PRO-PHE-ARG	0.085	1
AZOCASEIN	1.86	1
DANSYL-ALA-ALA-ARG-ALA-PRO-LEU-VAL	0.48	1

UniProt features (17 total): binding site 3, sequence variant 3, disulfide bond 2, region of interest 2, compositionally biased region 2, signal peptide 1, chain 1, helix 1, domain 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7ST8	X-RAY DIFFRACTION	2.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6HA08-F1	71.90	0.48

Antibody-complex structures (SAbDab): 1 — 7ST8

Functional residue map

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

Catalytic / active sites (1): 183

Ligand- & substrate-binding residues (3): 192; 182; 186

Disulfide bonds (2): 132–281, 153–172

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 67 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_MATURATION, GOBP_SINGLE_FERTILIZATION, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOMF_METALLOPEPTIDASE_ACTIVITY, GOCC_SECRETORY_GRANULE, GOBP_PROTEIN_MATURATION, GOBP_SPERM_EGG_RECOGNITION, GOBP_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_REGULATION_OF_PROTEIN_MATURATION, GOBP_POSITIVE_REGULATION_OF_PROTEOLYSIS, GOBP_FERTILIZATION, GOBP_CELL_CELL_RECOGNITION, GOBP_REGULATION_OF_PROTEOLYSIS, GOBP_BINDING_OF_SPERM_TO_ZONA_PELLUCIDA

GO Biological Process (7): proteolysis (GO:0006508), cell adhesion (GO:0007155), fertilization (GO:0009566), positive regulation of protein processing (GO:0010954), prevention of polyspermy (GO:0060468), negative regulation of binding of sperm to zona pellucida (GO:2000360), single fertilization (GO:0007338)

GO Molecular Function (9): metalloendopeptidase activity (GO:0004222), zinc ion binding (GO:0008270), aspartic-type peptidase activity (GO:0070001), glutamic-type peptidase activity (GO:0070002), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (6): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), plasma membrane (GO:0005886), cortical granule (GO:0060473), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidase activity	3
cellular anatomical structure	2
protein metabolic process	1
cellular process	1
sexual reproduction	1
reproductive process	1
protein processing	1
positive regulation of proteolysis	1
regulation of protein processing	1
positive regulation of protein maturation	1
egg activation	1
negative regulation of fertilization	1
binding of sperm to zona pellucida	1
negative regulation of cellular process	1
negative regulation of reproductive process	1
regulation of binding of sperm to zona pellucida	1
fertilization	1
endopeptidase activity	1
metallopeptidase activity	1
transition metal ion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
secretory granule	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

472 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASTL	ZP2	Q05996	780
ASTL	TIMP1	P01033	716
ASTL	FETUB	Q9UGM5	701
ASTL	ZP1	P60852	657
ASTL	ZP4	Q12836	656
ASTL	ZP3	P21754	632
ASTL	SPACA3	Q8IXA5	505
ASTL	LYZL6	O75951	479
ASTL	FAHD2B	Q6P2I3	447
ASTL	LYZL4	Q96KX0	445
ASTL	CRISP1	P54107	445
ASTL	PLCZ1	Q86YW0	441
ASTL	ANKRD39	Q53RE8	439
ASTL	FAM178B	Q8IXR5	434
ASTL	OOSP1	A8MZH6	433

IntAct

9 interactions, top by confidence:

A	B	Type	Score
CYSRT1	ASTL	psi-mi:“MI:0915”(physical association)	0.560
ASTL	HSPD1	psi-mi:“MI:0915”(physical association)	0.400
ASTL	VHL	psi-mi:“MI:0914”(association)	0.350
ASTL	HSPA5	psi-mi:“MI:0914”(association)	0.350
MAPK4	INPPL1	psi-mi:“MI:0914”(association)	0.350
ASTL	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): HSPA5 (Affinity Capture-MS), TUBB1 (Affinity Capture-MS), AMD1 (Affinity Capture-MS), JMJD8 (Affinity Capture-MS), VHL (Affinity Capture-MS), JMJD8 (Affinity Capture-MS), TUBB1 (Affinity Capture-MS), VHL (Affinity Capture-MS), CYSRT1 (Two-hybrid), ASTL (Negative Genetic), HSPA5 (Affinity Capture-MS), TUBB1 (Affinity Capture-MS), VHL (Affinity Capture-MS), JMJD8 (Affinity Capture-MS), ASTL (Affinity Capture-MS)

ESM2 similar proteins: A5A8Y8, A5PJC7, A6NKQ9, O75074, O88204, O95428, P0CG36, P0DV84, P37889, P39060, P39061, P47880, P55068, P97793, P98095, Q14162, Q28062, Q3UTY6, Q3UY90, Q4FZU4, Q5ND28, Q61361, Q61810, Q6GUQ1, Q6HA08, Q6UY14, Q6ZMP0, Q7TSK7, Q80T21, Q80W87, Q86TH1, Q8C310, Q8K1S7, Q8K4G1, Q8N2S1, Q8N441, Q8NCW0, Q8WUT4, Q8WZ75, Q91V98

Diamond homologs: A0A0C5PRQ1, A0FKN6, A8Q2D1, C9D7R2, C9D7R3, D2KBH9, D5FM34, D5FM37, D5FM38, K7Z9Q9, O16977, O17264, O43897, O57382, O57460, O62243, P07584, P0DM61, P0DM62, P13497, P28825, P28826, P31579, P31580, P31581, P42674, P55112, P55113, P55114, P55115, P84748, P91137, P98060, P98061, P98063, P98068, P98069, P98070, Q16819, Q16820

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	73
Likely benign	11
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1326900	NM_001002036.4(ASTL):c.456-1G>A	Pathogenic

SpliceAI

1269 predictions. Top by Δscore:

Variant	Effect	Δscore
2:96130141:AAAGC:A	acceptor_gain	1.0000
2:96130142:AAGC:A	acceptor_gain	1.0000
2:96130143:AGC:A	acceptor_gain	1.0000
2:96130143:AGCC:A	acceptor_loss	1.0000
2:96130144:GC:G	acceptor_gain	1.0000
2:96130145:CC:C	acceptor_gain	1.0000
2:96130145:CCTAA:C	acceptor_loss	1.0000
2:96130146:C:CC	acceptor_gain	1.0000
2:96130146:C:T	acceptor_gain	1.0000
2:96130146:CT:C	acceptor_loss	1.0000
2:96132535:CTCA:C	donor_loss	1.0000
2:96132536:TCA:T	donor_loss	1.0000
2:96132537:CACC:C	donor_loss	1.0000
2:96132538:A:C	donor_loss	1.0000
2:96132539:C:CT	donor_loss	1.0000
2:96132717:AGCAC:A	acceptor_gain	1.0000
2:96132719:CAC:C	acceptor_gain	1.0000
2:96132720:AC:A	acceptor_gain	1.0000
2:96132720:ACC:A	acceptor_loss	1.0000
2:96132721:CC:C	acceptor_gain	1.0000
2:96132722:C:CA	acceptor_loss	1.0000
2:96132722:C:CC	acceptor_gain	1.0000
2:96132725:C:CT	acceptor_gain	1.0000
2:96132729:G:C	acceptor_gain	1.0000
2:96132729:G:GC	acceptor_gain	1.0000
2:96133959:A:AC	donor_gain	1.0000
2:96133960:C:CC	donor_gain	1.0000
2:96133961:TCA:T	donor_loss	1.0000
2:96133962:CACCG:C	donor_loss	1.0000
2:96133963:A:AC	donor_gain	1.0000

AlphaMissense

2783 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:96134020:C:A	W94C	0.997
2:96134020:C:G	W94C	0.997
2:96129969:G:C	F243L	0.994
2:96129969:G:T	F243L	0.994
2:96129971:A:G	F243L	0.994
2:96130129:G:C	F218L	0.992
2:96130129:G:T	F218L	0.992
2:96130131:A:G	F218L	0.992
2:96133448:G:C	F144L	0.991
2:96133448:G:T	F144L	0.991
2:96133450:A:G	F144L	0.991
2:96132581:C:G	R199P	0.990
2:96132590:C:G	R196P	0.990
2:96130130:A:G	F218S	0.989
2:96134022:A:G	W94R	0.989
2:96134022:A:T	W94R	0.989
2:96132626:A:G	L184P	0.988
2:96132719:C:G	C153S	0.988
2:96132720:A:T	C153S	0.988
2:96129894:A:C	S268R	0.987
2:96129894:A:T	S268R	0.987
2:96129896:T:G	S268R	0.987
2:96132607:G:C	F190L	0.987
2:96132607:G:T	F190L	0.987
2:96132609:A:G	F190L	0.987
2:96130130:A:C	F218C	0.986
2:96129887:C:G	D271H	0.985
2:96132608:A:G	F190S	0.985
2:96132619:A:C	H186Q	0.985
2:96132619:A:T	H186Q	0.985

dbSNP variants (sampled 300 via entrez): RS1000100076 (2:96135918 G>A), RS1000321758 (2:96125108 C>A), RS1000409204 (2:96131559 A>AC), RS1000533572 (2:96136857 T>A), RS1000557890 (2:96130695 A>G), RS1000661109 (2:96131389 C>T), RS1000661502 (2:96124559 A>G), RS1000928559 (2:96130949 A>G), RS1001029909 (2:96137169 G>A), RS1001039333 (2:96137095 A>G), RS1001383643 (2:96124400 G>GA), RS1001446489 (2:96130238 T>A,G), RS1001581467 (2:96124094 A>G), RS1001750706 (2:96136800 C>T), RS1001922904 (2:96130855 C>T)

Disease associations

OMIM: gene MIM:608860 | disease phenotypes: MIM:619643

GenCC curated gene-disease

Disease	Classification	Inheritance
oocyte maturation defect 11	Limited	Autosomal recessive

Mondo (1): oocyte maturation defect 11 (MONDO:0030490)

Orphanet (0):

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0008222	Female infertility
HP:0011462	Young adult onset

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

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Lipopolysaccharides	increases expression, affects response to substance	1
Methapyrilene	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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