GNPTAB (GlcNAc-1-phosphotransferase alpha/beta subunits, UniProtKB:Q3T906) - review notes
Literature work for this review was done manually from the cached publications and
UniProt (no provider deep-research file was available when the review was written).
Biology
- GNPTAB encodes the alpha/beta-subunit precursor of UDP-GlcNAc:lysosomal enzyme
N-acetylglucosamine-1-phosphotransferase (EC 2.7.8.17), an alpha2beta2gamma2 hexamer
(gamma = GNPTG) that catalyses the first step of mannose 6-phosphate (M6P) formation on
high-mannose N-glycans of soluble lysosomal acid hydrolases in the Golgi
PMID:19955174.
- The alpha/beta subunits are the catalytic subunits and also recognise the protein
determinant on acid hydrolases PMID:19955174; the DMAP interaction domain is a substrate-recognition module
PMID:23733939, the Stealth domains harbour the catalytic site PMID:25505245.
- The precursor is a type III Golgi membrane protein cleaved by site-1 protease (MBTPS1)
into alpha and beta subunits, which is required for activity
PMID:21719679. The small Golgi membrane protein LYSET/TMEM251 binds
GNPTAB and is required for its stability, cleavage and Golgi retention PMID:36074821.
- GNPTG binds a dedicated GNPTG-binding domain on the alpha subunit
PMID:26385638.
- Location: Golgi membrane PMID:16200072.
Disease
Biallelic GNPTAB variants cause mucolipidosis II (I-cell disease; null alleles) and
mucolipidosis III alpha/beta (residual activity); hydrolases lacking M6P are hypersecreted
and lysosomes become deficient in many hydrolases PMID:16200072.
Curation decisions
- Core MF GO:0003976; core BP GO:0016256 N-glycan processing to lysosome (part_of
GO:0006622 protein targeting to lysosome); location Golgi membrane; complex GO:0070622.
- High-throughput Y2H/AP-MS "protein binding" partners (ZNF250, AEN, PSMA1, FAM90A1,
STAMBPL1, B3GALT2) have no functional support -> over-annotated. GNPTG and LYSET
interactions are functionally meaningful but are better represented by the complex term
and by LYSET's own annotations.