Affinage

MVB12A

Multivesicular body subunit 12A · UniProt Q96EY5

Length
273 aa
Mass
28.8 kDa
Annotated
2026-06-10
10 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MVB12A is the fourth, stoichiometric subunit of human ESCRT-I, completing a one-copy-each heterotetramer with TSG101, VPS28, and VPS37 through conserved C-terminal elements (PMID:18005716). Its MABP (MVB12-associated β-prism) domain directly engages acidic, phosphoinositide-containing membranes by sensing negative charge density rather than specific lipid head groups, using a hydrophobic anchoring loop and an electropositive patch, and is sufficient to localize autonomously to puncta and the plasma membrane (PMID:22232651). Through this membrane-sensing module MVB12A-containing ESCRT-I is functionally distinct from the endosome-specific UBAP1–VPS37A complex and is not required for ubiquitin-dependent MVB cargo sorting, marking a division of labor among ESCRT-I variants defined by their MVB12-family subunit (PMID:21757351, PMID:24284069). Within the assembled complex, MVB12A is part of an ESCRT-I helical scaffold with a 12-molecule repeat whose integrity is required for autophagosome closure and HIV-1 release, giving ESCRT-I a mechanical scaffolding role in membrane scission (PMID:32424346), and MVB12A is specifically required for β-coronavirus egress but not virion assembly (PMID:40407327). EGF-induced phosphorylation of MVB12A at Tyr204 modulates its binding to CD2AP and thereby tunes the amount of EGF receptor associated with ESCRT-I (PMID:20654576).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2007 High

    Established that metazoan ESCRT-I is a heterotetramer by identifying MVB12A/B as a fourth subunit class, defining the complex's composition and a role in viral budding.

    Evidence Hydrodynamic analysis, reciprocal co-immunoprecipitation, and siRNA/overexpression with HIV-1 infectivity and morphology readouts

    PMID:18005716

    Open questions at the time
    • Did not resolve how MVB12A contacts membranes
    • Mechanism of the budding defect at the structural level unresolved
  2. 2010 Medium

    Connected MVB12A to receptor-level signaling by showing EGF-triggered Tyr204 phosphorylation regulates CD2AP binding and the loading of EGFR onto ESCRT-I.

    Evidence Phospho-site mutagenesis, co-immunoprecipitation, and EGF/ubiquitination assays in COS-7 cells

    PMID:20654576

    Open questions at the time
    • Single lab, no independent replication
    • Kinase responsible for Tyr204 phosphorylation not identified
    • Functional consequence for cargo fate not measured
  3. 2011 High

    Resolved that ESCRT-I exists in functionally specialized variants by showing UBAP1/VPS37A — excluding MVB12A/B — drives endosomal MVB sorting and ubiquitin homeostasis.

    Evidence siRNA depletion, co-immunoprecipitation, and EGFR degradation / ubiquitin homeostasis assays

    PMID:21757351

    Open questions at the time
    • Did not define the positive cellular role of MVB12A-containing ESCRT-I
    • Basis of subunit-selective complex assembly unresolved
  4. 2012 High

    Defined the molecular basis of MVB12A membrane recognition, revealing the MABP β-prism domain as a charge-density-sensing membrane anchor.

    Evidence 1.3-Å crystal structure of the MVB12B MABP domain, in vitro liposome-binding, and subcellular localization imaging

    PMID:22232651

    Open questions at the time
    • In vivo contribution of MABP binding within the intact ESCRT-I complex not directly tested
    • How charge-sensing integrates with cargo recognition unresolved
  5. 2013 High

    Confirmed selective incorporation of MVB12A with specific VPS37 partners and that its loss leaves ubiquitin-dependent MVB sorting intact, cementing a distinct function from UBAP1-VPS37A complexes.

    Evidence siRNA depletion, co-immunoprecipitation, domain mapping, and MVB cargo-sorting assays

    PMID:24284069

    Open questions at the time
    • Positive cargo or process uniquely served by MVB12A-ESCRT-I not identified
    • Rules governing VPS37-MVB12 pairing not fully defined
  6. 2020 High

    Revealed that MVB12A-containing ESCRT-I forms a helical filament scaffold with mechanical function, not merely a bridging adaptor, linking it to membrane scission.

    Evidence Crystal structure of TSG101-VPS28-VPS37B-MVB12A headpiece, EM, in vitro filament assay, VPS28 interface mutagenesis with autophagosome closure and HIV-1 budding readouts

    PMID:32424346

    Open questions at the time
    • Specific contribution of MVB12A to filament mechanics not isolated from other subunits
    • How the helical scaffold templates ESCRT-III not fully resolved
  7. 2025 Medium

    Placed MVB12A specifically at the egress step of the β-coronavirus life cycle, distinguishing it from virion assembly.

    Evidence siRNA knockdown of MVB12A with EM of assembly and virion-like-particle / replication egress assays for OC43

    PMID:40407327

    Open questions at the time
    • Single study, no independent replication
    • Molecular target of MVB12A at the egress membrane unidentified
    • Whether the MABP domain mediates the egress role untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The endogenous cellular cargo or membrane process uniquely dependent on MVB12A-containing ESCRT-I — as opposed to its role in viral budding and autophagosome closure — remains undefined.
  • No cellular substrate specific to MVB12A-ESCRT-I identified
  • Physiological signal controlling Tyr204 phosphorylation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0005198 structural molecule activity 1 GO:0008289 lipid binding 1
Localization
GO:0005768 endosome 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1643685 Disease 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9612973 Autophagy 1
Partners
CD2APMVB12BTSG101VPS28VPS37B
Complex memberships
ESCRT-I

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 MVB12A (and MVB12B) are identified as the fourth class of metazoan ESCRT-I subunits, forming a stoichiometric heterotetramer (one copy each) with TSG101, VPS28, and VPS37. MVB12 subunits associate with the core region of the binary TSG101-VPS37 complex through conserved C-terminal sequence elements. Both depletion and overexpression of MVB12 inhibit HIV-1 infectivity and induce aberrant virion morphologies and altered Gag protein processing. Hydrodynamic studies, co-immunoprecipitation, siRNA depletion, overexpression, viral infectivity and morphology assays Cell host & microbe High 18005716
2010 Tyrosine-204 phosphorylation of MVB12A in response to EGF stimulation affects its binding to CD2AP, which in turn regulates the amount of EGF receptor bound to ESCRT-I. MVB12A is also involved in the aggregation of the ubiquitination-prone MVB12B protein. Phosphorylation site mutagenesis, co-immunoprecipitation, EGF stimulation assays, ubiquitination assays in COS-7 cells Biochemical and biophysical research communications Medium 20654576
2011 UBAP1 defines an endosome-specific ESCRT-I complex that contains VPS37A but excludes MVB12A/MVB12B. UBAP1 (not MVB12A/B) is required for MVB sorting of EGFR and endosomal ubiquitin homeostasis, establishing that ESCRT-I variants with different MVB12-family members have distinct functional specializations. siRNA depletion, co-immunoprecipitation, EGFR degradation assay, ubiquitin homeostasis assay Current biology : CB High 21757351
2012 The MABP (MVB12-associated β-prism) domain of MVB12A and MVB12B binds acidic lipid-containing liposomes in vitro in a negative-charge-density-dependent manner and autonomously localizes to subcellular puncta and the plasma membrane. The 1.3-Å crystal structure of the MVB12B MABP domain reveals a β-prism fold with a hydrophobic membrane-anchoring loop and an electropositive phosphoinositide-binding patch that senses charge density without lipid-head-group stereoselectivity. Crystal structure determination (1.3 Å), in vitro liposome-binding assay, subcellular localization imaging Proceedings of the National Academy of Sciences of the United States of America High 22232651
2013 The incorporation of MVB12A into ESCRT-I is highly selective with respect to its VPS37 partner. siRNA-mediated depletion of MVB12A (and MVB12B together) does not disrupt ubiquitin-dependent MVB sorting, in contrast to UBAP1 depletion, demonstrating that MVB12A-containing ESCRT-I is functionally distinct from the UBAP1-VPS37A endosome-specific complex. siRNA depletion, co-immunoprecipitation, domain-mapping experiments, MVB cargo-sorting assays Journal of cell science High 24284069
2020 Crystal structure of the human ESCRT-I headpiece comprising TSG101-VPS28-VPS37B-MVB12A reveals that ESCRT-I forms a helical assembly with a 12-molecule repeat. ESCRT-I subcomplexes form helical filaments in solution (confirmed by EM). Mutation of VPS28 helical interface residues blocks filament formation in vitro and impairs autophagosome closure and HIV-1 release in human cells, demonstrating that ESCRT-I has an essential scaffolding and mechanical role beyond bridging. Crystal structure determination, electron microscopy, in vitro filament formation assay, VPS28 interface mutagenesis, autophagosome closure assay, HIV-1 budding assay Nature structural & molecular biology High 32424346
2025 Knockdown of MVB12A does not affect β-coronavirus (OC43) virion assembly but inhibits virion egress, placing MVB12A specifically in the egress step of the ESCRT-dependent coronavirus life cycle. siRNA knockdown, electron microscopy of virion assembly, virion-like particle production assay, coronavirus replication assay mBio Medium 40407327

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting. Current biology : CB 110 21757351
2007 Identification of human MVB12 proteins as ESCRT-I subunits that function in HIV budding. Cell host & microbe 99 18005716
2020 A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission. Nature structural & molecular biology 48 32424346
2012 Structural basis for membrane targeting by the MVB12-associated β-prism domain of the human ESCRT-I MVB12 subunit. Proceedings of the National Academy of Sciences of the United States of America 43 22232651
2013 The molecular basis for selective assembly of the UBAP1-containing endosome-specific ESCRT-I complex. Journal of cell science 30 24284069
2010 Distinct functions of human MVB12A and MVB12B in the ESCRT-I dependent on their posttranslational modifications. Biochemical and biophysical research communications 26 20654576
2022 Transcriptome Analysis Reveals Hub Genes Regulating Autophagy in Patients With Severe COVID-19. Frontiers in genetics 10 35923698
2025 β-Coronaviruses exploit ESCRT for virion assembly and egress. mBio 2 40407327
2026 Positive effects of bile acids alleviating heat stress in laying hens by enhancing immunity via metabolome and transcriptome integration. Poultry science 1 41558077
2026 Distinct tumor genomic signatures underlie canine macrophage polarization. PloS one 0 42030266

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