Affinage

TMUB2

Transmembrane and ubiquitin-like domain-containing protein 2 · UniProt Q71RG4

Round 2 corrected
Length
321 aa
Mass
33.8 kDa
Annotated
2026-04-28
28 papers in source corpus 2 papers cited in narrative 2 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMUB2 is a transmembrane and ubiquitin-like domain-containing ER membrane protein that functions as a component of the RNF185/Membralin ERAD complex, together with TMUB1, TMEM259/Membralin, the ubiquitin ligase RNF185, the cytosolic ubiquitin ligase UBE3C, and the p97 ATPase, to mediate quality-control degradation of a specific subset of misfolded ER membrane substrates (PMID:32738194). This complex defines a dedicated branch of ER-associated degradation (ERAD) specialized for membrane protein substrates, as established by CRISPR-Cas9 genome-wide screening and biochemical reconstitution (PMID:32738194).

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2016 Low

    Before TMUB2's ER quality-control role was known, a yeast two-hybrid screen identified it as a binding partner of the oncogenic phosphatases PRL-1 and PRL-3, providing the first reported physical interaction for this protein.

    Evidence Yeast two-hybrid screening

    PMID:27882103

    Open questions at the time
    • Interaction was not independently validated for TMUB2 by reciprocal or orthogonal methods
    • Functional significance of the TMUB2–PRL interaction is unexplored
    • No in vivo or endogenous-level confirmation
  2. 2020 High

    A genome-wide CRISPR screen and biochemical dissection revealed that TMUB2 is an integral component of a previously unrecognized RNF185/Membralin ER membrane complex that, together with UBE3C and p97, degrades misfolded ER membrane proteins — establishing TMUB2's primary function in a specific ERAD branch.

    Evidence CRISPR-Cas9 genome-wide library screen, co-immunoprecipitation, mass spectrometry, and functional degradation assays in human cells

    PMID:32738194

    Open questions at the time
    • The specific molecular contribution of TMUB2's ubiquitin-like domain within the complex is undefined
    • Whether TMUB2 and TMUB1 have redundant or distinct substrate-selection roles is unresolved
    • No structural model of the RNF185/Membralin complex including TMUB2 is available

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include whether TMUB2's ubiquitin-like domain directly engages ubiquitin-binding partners to recruit substrates or cofactors, what distinguishes TMUB2 from TMUB1 within the complex, and whether loss of TMUB2 contributes to disease phenotypes.
  • No direct enzymatic or structural role assigned to TMUB2 itself
  • Physiological consequences of TMUB2 loss in organismal models are unexplored
  • Relationship between the reported PRL interaction and ERAD function is unexamined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-392499 Metabolism of proteins 1
Partners
RNF185TMEM259TMUB1UBE3C
Complex memberships
RNF185/Membralin ERAD complex

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 TMUB1 and TMUB2 (ubiquitin-like domain-containing proteins) are components of an ER membrane ERAD complex together with the ubiquitin ligase RNF185 and TMEM259/Membralin. This complex, identified by CRISPR-Cas9 genome-wide screening and biochemical/mass spectrometry approaches, cooperates with cytosolic ubiquitin ligase UBE3C and the p97 ATPase to degrade a subset of misfolded ER membrane proteins, defining a specific branch of ERAD for membrane substrate quality control. CRISPR-Cas9 genome-wide library screen, co-immunoprecipitation, mass spectrometry, biochemical degradation assays Molecular cell High 32738194
2016 TMUB2 (transmembrane and ubiquitin-like domain-containing 2) was identified as a binding partner of oncogenic phosphatases PRL-1 and PRL-3 via yeast two-hybrid screening, placing TMUB2 in the context of PRL-family-mediated signaling. Yeast two-hybrid screening Experimental and therapeutic medicine Low 27882103

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2003 The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome research 285 12975309
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
2001 Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs. Genome research 151 11230166
2017 The STUbL RNF4 regulates protein group SUMOylation by targeting the SUMO conjugation machinery. Nature communications 86 29180619
2004 Large-scale cDNA transfection screening for genes related to cancer development and progression. Proceedings of the National Academy of Sciences of the United States of America 82 15498874
2020 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell reports 79 32814053
2020 Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling. eLife 70 32614325
2017 Systematic protein-protein interaction mapping for clinically relevant human GPCRs. Molecular systems biology 58 28298427
1996 A "double adaptor" method for improved shotgun library construction. Analytical biochemistry 53 8619474
2020 Quality Control of ER Membrane Proteins by the RNF185/Membralin Ubiquitin Ligase Complex. Molecular cell 52 32738194
1997 Large-scale concatenation cDNA sequencing. Genome research 45 9110174
2004 From ORFeome to biology: a functional genomics pipeline. Genome research 38 15489336
2022 A BioID-Derived Proximity Interactome for SARS-CoV-2 Proteins. Viruses 37 35337019
2020 Global proteomics of Ubqln2-based murine models of ALS. The Journal of biological chemistry 37 33277362
2006 The LIFEdb database in 2006. Nucleic acids research 29 16381901
2020 EDEM1 Drives Misfolded Protein Degradation via ERAD and Exploits ER-Phagy as Back-Up Mechanism When ERAD Is Impaired. International journal of molecular sciences 26 32423001
2025 The solute carrier superfamily interactome. Molecular systems biology 9 40355756
2016 Identification of proteins suppressing the functions of oncogenic phosphatase of regenerating liver 1 and 3. Experimental and therapeutic medicine 6 27882103