Affinage

TRAPPC2

Trafficking protein particle complex subunit 2 · UniProt P0DI81

Length
140 aa
Mass
16.4 kDa
Annotated
2026-04-28
18 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRAPPC2 (Sedlin) is a core adaptor subunit of the TRAPP trafficking complex that bridges the shared TRAPP core to complex-specific subunits, thereby enabling assembly of both TRAPPII (via interaction with TRAPPC9/Trs120 and TRAPPC10/Trs130) and TRAPPIII (via interaction with TRAPPC8/Trs85), and consequently supporting their Rab/Ypt GEF activities, ER-to-Golgi transport, and autophagy (PMID:21858081, PMID:23465091, PMID:24329977). TRAPPC2 also binds the SNARE protein Syntaxin 5, and the spondyloepiphyseal dysplasia tarda (SEDT)-causing D47Y missense mutation abolishes interactions with both complex-specific TRAPP subunits and Syntaxin 5, establishing this residue as a critical binding interface (PMID:21858081, PMID:23898804). Loss of TRAPPC2 in chondrocytes impairs collagen II expression and secretion, providing a direct mechanistic link between TRAPPC2-dependent vesicular trafficking and the cartilage defect in X-linked SEDT (PMID:37693308).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2011 High

    Establishing how higher-order TRAPP complexes are assembled, this study showed TRAPPC2 acts as a bridging adaptor that independently recruits TRAPPII-specific (TRAPPC9) and TRAPPIII-specific (TRAPPC8) subunits to the core complex, with the SEDT mutation D47Y abolishing both interactions.

    Evidence Co-immunoprecipitation in mammalian cells with wild-type and D47Y mutant TRAPPC2

    PMID:21858081

    Open questions at the time
    • Structural basis of the D47-mediated interface not resolved at atomic level
    • Whether TRAPPC2 bridges both complexes simultaneously or in separate pools is unclear
    • Functional consequences for vesicular trafficking not directly measured in this study
  2. 2013 High

    The adaptor role of TRAPPC2 was validated in yeast and extended to GEF function and SNARE binding: Trs20/TRAPPC2 is required for TRAPPII assembly and its Ypt32 GEF activity, and mammalian TRAPPC2 binds Syntaxin 5 — both interactions being disrupted by the D46Y/D47Y SEDT mutation.

    Evidence In vitro GEF assays and Co-IP with yeast D46Y mutant; mammalian Co-IP for TRAPPC2–Syntaxin 5; autophagy assays in yeast trs20 mutants

    PMID:23465091 PMID:23898804

    Open questions at the time
    • Whether the Syntaxin 5 interaction is direct or mediated through TRAPP complex context
    • Relative contribution of TRAPPII vs TRAPPIII disruption to the SEDT disease phenotype unclear
  3. 2014 High

    TRAPPC2/Trs20 was shown to be essential for TRAPPIII complex assembly at the pre-autophagosomal structure, establishing it as a critical node linking vesicular trafficking to both selective and non-selective autophagy.

    Evidence Recombinant protein co-precipitation, in vitro GEF assay, live-cell colocalization, and autophagy assays in yeast trs20ts mutants

    PMID:24329977

    Open questions at the time
    • Whether mammalian TRAPPC2 loss similarly impairs autophagy in relevant tissues not yet shown
    • Mechanism by which TRAPPC2-dependent TRAPPIII is recruited specifically to PAS membranes is unresolved
  4. 2023 Medium

    Connecting TRAPPC2 function to the tissue-specific SEDT phenotype, TRAPPC2 knockdown in chondrocytes was shown to reduce collagen II expression and secretion, demonstrating a direct role in procollagen trafficking.

    Evidence siRNA knockdown in SW1353 cells and primary human chondrocytes; Western blot and ELISA for collagen II; patient nonsense variant analysis

    PMID:37693308

    Open questions at the time
    • Whether collagen II reduction is due to ER retention, degradation, or transcriptional effects not fully resolved
    • Other cargo affected by TRAPPC2 loss in chondrocytes not catalogued
    • No in vivo animal model validation of the chondrocyte secretion defect

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the atomic-resolution structure of TRAPPC2 at the TRAPPII/III assembly interface, the mechanism by which TRAPPC2 loss causes tissue-restricted skeletal pathology despite its ubiquitous expression, and whether TRAPPC2-dependent autophagy defects contribute to SEDT pathogenesis.
  • No high-resolution structure of TRAPPC2 in complex with TRAPPC9 or TRAPPC8
  • Tissue-specific vulnerability mechanism for SEDT not explained
  • Whether autophagy defects contribute to chondrocyte dysfunction in SEDT is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005794 Golgi apparatus 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9612973 Autophagy 2
Partners
STX5TRAPPC10TRAPPC8TRAPPC9
Complex memberships
TRAPPIITRAPPIII

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 TRAPPC2 (Sedlin) serves as an adaptor protein for the formation of mammalian TRAPPII and TRAPPIII complexes: TRAPPC2 binds to TRAPPII-specific subunit TRAPPC9 (which in turn binds TRAPPC10), and also binds TRAPPIII-specific subunit TRAPPC8. The disease-causing mutation D47Y abolishes these interactions, demonstrating that aspartate 47 is at or near the binding interface with TRAPPC9 and TRAPPC8. Co-immunoprecipitation in mammalian cells; disease-causing mutant D47Y used to map functional interface PloS one High 21858081
2013 Yeast Trs20 (ortholog of TRAPPC2/Sedlin) is required for TRAPPII assembly: Trs20 interacts with TRAPPII-specific subunit Trs120, and the SEDT-equivalent mutation D46Y prevents this interaction, thereby blocking TRAPPII assembly and its Ypt32 guanine-nucleotide exchange factor (GEF) activity. In vitro GEF assay, co-immunoprecipitation, SEDT-equivalent mutant (D46Y) analysis in yeast Traffic (Copenhagen, Denmark) High 23465091
2014 Yeast Trs20 (ortholog of TRAPPC2/Sedlin) is required for TRAPPIII complex assembly at the pre-autophagosomal structure (PAS): recombinant Trs85 (TRAPPIII-specific subunit) associates with TRAPP only in the presence of Trs20 but not the D46Y mutant; live-cell colocalization shows Trs85 recruits core TRAPP to the PAS via Trs20; trs20ts mutants are defective in both selective and non-selective autophagy. Recombinant protein co-precipitation, in vitro GEF assay, live-cell colocalization imaging, autophagy assays in yeast trs20ts mutants Traffic (Copenhagen, Denmark) High 24329977
2013 TRAPPC2 (C2/Sedlin) binds to the SNARE protein Syntaxin 5, and this interaction is weakened by the SEDT-causing missense mutation D47Y; the equivalent yeast mutation D46Y in Trs20 also interferes with interaction with Trs85 (TRAPPIII-specific), Trs120, and Trs130 (TRAPPII-specific subunits), and destabilizes the TRAPPIII complex involved in autophagy, blocking both the cytosol-to-vacuole (cvt) pathway and non-selective autophagy. Co-immunoprecipitation (TRAPPC2–Syntaxin 5 in mammalian cells), yeast mutant D46Y interaction studies, size exclusion chromatography, autophagy assays Traffic (Copenhagen, Denmark) High 23898804
2023 TRAPPC2 knockdown in SW1353 cells or primary human chondrocytes results in decreased COL2A1 (collagen II) expression and secretion; a nonsense variant (c.91A>T) that reduces TRAPPC2 protein levels also alters its membrane distribution, linking TRAPPC2 function to procollagen/collagen secretion in chondrocytes. siRNA knockdown of TRAPPC2 in chondrocyte cell lines and primary chondrocytes, Western blot for COL2A1, ELISA for secreted collagen II, cell fluorescence for subcellular localization Frontiers in genetics Medium 37693308
2024 Human TRAPPC2 can functionally replace its yeast ortholog Trs20 in Saccharomyces cerevisiae (humanized yeast model), confirming conservation of its essential function in the TRAPP complex across species. CRISPR/Cas9-mediated humanization of yeast (replacement of yeast TRS20 with human TRAPPC2), functional complementation assay bioRxivpreprint Medium bio_10.1101_2024.08.04.605925

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 The adaptor function of TRAPPC2 in mammalian TRAPPs explains TRAPPC2-associated SEDT and TRAPPC9-associated congenital intellectual disability. PloS one 54 21858081
2014 Trs20 is required for TRAPP III complex assembly at the PAS and its function in autophagy. Traffic (Copenhagen, Denmark) 29 24329977
2013 A trs20 mutation that mimics an SEDT-causing mutation blocks selective and non-selective autophagy: a model for TRAPP III organization. Traffic (Copenhagen, Denmark) 23 23898804
2013 Trs20 is required for TRAPP II assembly. Traffic (Copenhagen, Denmark) 20 23465091
2003 Modulation of human luteinizing hormone beta gene transcription by MIP-2A. The Journal of biological chemistry 11 12700240
2013 Whole exome sequencing and functional studies identify an intronic mutation in TRAPPC2 that causes SEDT. Clinical genetics 9 23656395
2012 X-linked spondyloepiphyseal dysplasia tarda: Identification of a TRAPPC2 mutation in a Korean pedigree. Annals of laboratory medicine 9 22563562
2007 Mutant WISP3 triggers the phenotype shift of articular chondrocytes by promoting sensitivity to IGF-1 hypothesis of spondyloepiphyseal dysplasia tarda with progressive arthropathy (SEDT-PA). Medical hypotheses 8 17363178
2020 A novel deletion variant in TRAPPC2 causes spondyloepiphyseal dysplasia tarda in a five-generation Chinese family. BMC medical genetics 7 32471379
2019 Novel loss-of-function variants of TRAPPC2 manifesting X-linked spondyloepiphyseal dysplasia tarda: report of two cases. BMC medical genetics 6 31053099
2013 MIP-2A is a novel target of an anilinoquinazoline derivative for inhibition of tumour cell proliferation. PloS one 5 24098805
2014 Novel TRAPPC2 mutation in a boy with X-linked spondylo-epiphyseal dysplasia tarda. Pediatrics international : official journal of the Japan Pediatric Society 4 25521980
2021 A novel missense variant in TRAPPC2 causes X-linked spondyloepiphyseal dysplasia tarda: A case report. Medicine 2 33726005
2015 [Mutation analysis of the TRAPPC2 gene in a Chinese family with X-linked spondyloepiphyseal dysplasia tarda]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 26252088
2023 Functional analysis of a novel nonsense variant c.91A>T of the TRAPPC2 gene in a Chinese family with X-linked recessive autosomal spondyloepiphyseal dysplasia tarda. Frontiers in genetics 1 37693308
2008 [Construction of WISP3 gene's mutants in SEDT-PA and their expression in COS-7 cells]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 1 18245897
2026 Identification and functional analysis of a novel TRAPPC2 intronic variant in a four-generation Chinese pedigree with SEDT. Frontiers in genetics 0 41732158
2024 A Novel Premature Termination Codon Mutation in TRAPPC2 Is Associated with X-Linked Spondyloepiphyseal Dysplasia Tarda. Molecular syndromology 0 41059451