UniProt: O96007 (MOC2B_HUMAN, "Molybdopterin synthase catalytic subunit"). HGNC:7193. Gene ID 4338.
MOCS2 is a bicistronic gene producing two proteins from overlapping reading frames:
- MOCS2A (small subunit; UniProt O96033) — a ubiquitin-like sulfur-carrier protein whose C-terminal thiocarboxylate (Gly-Gly → Gly-aminoethanethioate) delivers sulfur.
- MOCS2B (large / catalytic subunit; UniProt O96007, this entry) — the MoaE-family catalytic subunit.
[file:human/MOCS2/MOCS2-uniprot.txt "This protein is produced by a bicistronic gene which also produces the small subunit (MOCS2A) from an overlapping reading frame. Expression of these 2 proteins are related since a mutation that removes the start codon of the small subunit (MOCS2A) also impairs expression of the large subunit (MOCS2B)."]
First reported as a bicistronic transcript with overlapping reading frames by Stallmeyer et al. PMID:10053003 and Sloan et al. PMID:9889283.
MOCS2B is the catalytic subunit of the molybdopterin (MPT) synthase complex, which catalyses the second step of molybdenum cofactor (MoCo) biosynthesis: conversion of cyclic pyranopterin monophosphate (cPMP / precursor Z / compound Z) to molybdopterin (MPT) by insertion of two sulfur atoms into the pterin to form the dithiolene group that chelates molybdenum.
[file:human/MOCS2/MOCS2-uniprot.txt "Catalytic subunit of the molybdopterin synthase complex, a complex that catalyzes the conversion of precursor Z into molybdopterin. Acts by mediating the incorporation of 2 sulfur atoms from thiocarboxylated MOCS2A into precursor Z to generate a dithiolene group"]
Mechanistic / catalytic characterization: Leimkuhler et al. PMID:12732628 — this paper also mapped disease mutations: MOCS2A-V7F weakens the MOCS2A–MOCS2B interaction; MOCS2B-E168K attenuates binding of precursor Z PMID:12732628.
Physiological role of the upstream sulfurtransferase (MOCS3) that charges MOCS2A: Matthies et al. PMID:15073332. Same paper establishes cytosolic localization PMID:15073332.
Edwards et al. PMID:25709896 provide human-recombinant functional data: WT MOCS2B binds MOCS2A (Kd = 0.36 μM) and supports MPT synthesis; the disease mutant MOCS2B-S140F disrupts complex assembly and abolishes activity PMID:25709896. This paper is the basis for the recent IDA MF/BP/CC annotations (2025 dates in GOA).
Heterotetramer: (MOCS2A)2(MOCS2B)2. [file:human/MOCS2/MOCS2-uniprot.txt "Heterotetramer; composed of 2 small (MOCS2A) and 2 large (MOCS2B) subunits"] — homologous to E. coli MoaD (small) / MoaE (large). GO CC: GO:1990140 molybdopterin synthase complex (ComplexPortal CPX-6341).
MOCS2B ↔ MOCS2A interaction confirmed by ITC and biochemistry PMID:25709896, and reported in the mutation-mapping papers PMID:12732628, PMID:16021469. The GOA "protein binding" (GO:0005515) IPI entries against MOCS2A (O96033) capture this same subunit–subunit interaction; the specific, informative representation is the molybdopterin synthase complex CC + molybdopterin synthase activity MF, so the bare "protein binding" entries are best marked as over-annotations.
Cytosol (GO:0005829), with the whole MPT synthase machinery localized there PMID:15073332. HPA IDA and PMID:26705305 IDA also support cytosol. A nucleus annotation (GO:0005634) comes from PMID:26705305 (IDA) and UniProt-SubCell IEA; the UniProt record lists Nucleus as a secondary location, tied to the moonlighting PKR/ATAC role.
Suganuma et al. PMID:26705305 report that human MPT synthase plus the ATAC acetyltransferase complex bind and inhibit the stress kinase PKR (EIF2AK2), suppressing eIF2α/JNK phosphorylation and thereby promoting translation initiation of iron-responsive mRNAs PMID:26705305. This underlies:
- GO:0009968 negative regulation of signal transduction (IDA) — a real but secondary/moonlighting activity, keep as non-core.
- GO:0005515 protein binding IPI vs EIF2AK2/PKR (Q9NS73) and MBIP.
- GO:0005634 nucleus (IDA).
These are genuine experimental findings but are not the canonical MoCo-biosynthesis core function; treat as KEEP_AS_NON_CORE / MARK_AS_OVER_ANNOTATED (for the bare "protein binding").
Molybdenum cofactor deficiency, type B / B1 (MOCODB1; MIM 252160) — autosomal recessive; neonatal intractable seizures, opisthotonus, facial dysmorphism, hypouricemia, elevated urinary sulfite / S-sulfocysteine; severe neurologic damage, often lethal in early childhood. [file:human/MOCS2/MOCS2-uniprot.txt "Molybdenum cofactor deficiency, type B1 (MOCODB1)"]. Compound Z (oxidation product of cPMP) accumulates in urine in MOCS2 deficiency, and exogenous cPMP is NOT effective (unlike MOCS1 deficiency) PMID:25709896. Many disease-variant reports (Reiss, Hahnewald, etc.); GO does not annotate the disease directly (captured via variants), so no BP term for disease is expected.
contributes_to IDA entries are appropriate (activity requires both subunits) — ACCEPT/KEEP.