Affinage

GCC1

GRIP and coiled-coil domain-containing protein 1 · UniProt Q96CN9

Length
775 aa
Mass
87.8 kDa
Annotated
2026-06-10
26 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GCC1 (GCC88) is a peripheral trans-Golgi network (TGN) golgin that tethers a specific class of endosome-derived retrograde transport carriers to maintain TGN-directed cargo recycling and lysosomal function (PMID:17914056, PMID:30559172). It targets the TGN through its C-terminal GRIP (GLD) domain, which depends on two conserved aromatic residues and binds membrane determinants distinct from the Arl1-dependent GRIP golgins, recruiting GCC88 to a functionally distinct TGN subcompartment (PMID:10209125, PMID:15522892). GCC88 assembles exclusively as parallel coiled-coil homodimers and does not heterodimerize with other GRIP-domain golgins (PMID:15654769), while a short 20–50 residue motif at its extreme N-terminus is necessary and sufficient to capture endosome-to-Golgi carriers, using a determinant distinct from golgin-97 and golgin-245 (PMID:28122620). Functionally, GCC88 defines a syntaxin 6-dependent retrograde route from early endosomes to the TGN for TGN38 and the cation-independent mannose-6-phosphate receptor (CI-M6PR), a pathway separable from the Shiga toxin route and dependent on retromer/SNX3 but not SNX27 or SNX-BAR proteins (PMID:17914056, PMID:30559172). Loss of GCC88 strands these cargoes in early endosomes, lowers steady-state CI-M6PR, impairs cathepsin-D processing, and reduces lysosomal proteolytic capacity without affecting autophagy (PMID:30791178). Beyond carrier tethering, GCC88 binds the long isoform of intersectin-1 (ITSN-1), a Cdc42 GEF, at the TGN to link the Golgi to the actin cytoskeleton via non-muscle myosin IIA and thereby regulate Golgi ribbon architecture (PMID:30540523).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1999 High

    Established how GCC88 is targeted to the Golgi, identifying the C-terminal GRIP domain and the specific residues required for membrane localization.

    Evidence GFP chimera transfection and site-directed mutagenesis of conserved aromatic residues in mammalian cells

    PMID:10209125

    Open questions at the time
    • Did not identify the membrane determinant the GRIP domain binds
    • Did not address the function of the rest of the protein
  2. 2002 High

    Placed GCC88 at the TGN as a peripheral membrane protein and implicated its N-terminal domain in organizing a syntaxin 6/TGN38-containing TGN subcompartment.

    Evidence Immunofluorescence, immunoelectron microscopy, and domain-truncation overexpression in HeLa cells

    PMID:12446665

    Open questions at the time
    • Overexpression-induced structures may not reflect endogenous architecture
    • N-terminal domain function not yet linked to specific cargo capture
  3. 2004 High

    Distinguished GCC88 from other GRIP golgins by showing it does not require Arl1 and occupies a non-overlapping TGN domain, establishing functional segregation of golgins at the TGN.

    Evidence Overexpression, IFM/IEM, and in vivo Arl1 interaction assays

    PMID:12416725 PMID:15522892

    Open questions at the time
    • The actual GCC88 GRIP membrane receptor remained unidentified
    • Functional consequence of the distinct TGN domain not yet defined
  4. 2005 High

    Defined the quaternary structure of GCC88 as an exclusive parallel coiled-coil homodimer, explaining how it forms an extended tether without mixing with other golgins.

    Evidence Co-immunoprecipitation, chemical cross-linking, and yeast two-hybrid of tagged fragments

    PMID:15654769

    Open questions at the time
    • No high-resolution structure of the coiled-coil
    • Did not test how dimerization relates to cargo capture
  5. 2007 High

    Demonstrated that GCC88 defines a specific syntaxin 6-dependent retrograde pathway from early endosomes to the TGN, distinct from the Shiga toxin route.

    Evidence siRNA knockdown in HeLa cells with TGN38/CD8-M6PR-tail cargo assays and syntaxin 6 rescue

    PMID:17914056

    Open questions at the time
    • Did not identify the carrier-capture motif on GCC88
    • Molecular link between GCC88 and syntaxin 6 not resolved
  6. 2017 High

    Mapped the cargo-capture function to a minimal extreme N-terminal motif and showed it captures a different carrier class than golgin-97/245, establishing GCC88 as a selective tether.

    Evidence Ectopic relocalization capture assay with systematic domain mapping across golgins

    PMID:28122620

    Open questions at the time
    • Carrier coat/receptor recognized by this motif not identified
    • Ectopic assay does not prove the native capture interaction
  7. 2018 High

    Resolved cargo and machinery selectivity by showing GCC88 selectively tethers retromer/SNX3-dependent CI-M6PR carriers and separately links the TGN to actin via the ITSN-1/Cdc42/myosin IIA axis to control Golgi ribbon architecture.

    Evidence Vps35 knockout with cargo tethering assays and SNX epistasis; reciprocal Co-IP, MS, and knockdown with morphological readouts

    PMID:30540523 PMID:30559172

    Open questions at the time
    • Direct biochemical contact between GCC88 and retromer/SNX3 not demonstrated
    • How carrier tethering and the actin-linking role are coordinated is unclear
  8. 2019 High

    Connected GCC88-dependent CI-M6PR retrieval to downstream lysosomal physiology, showing its loss impairs cathepsin-D processing and lysosomal proteolytic capacity but not autophagy.

    Evidence CRISPR/Cas9 knockout with CI-M6PR trafficking, cathepsin-D processing, and lysosomal activity assays

    PMID:30791178

    Open questions at the time
    • Did not test broader hydrolase repertoire beyond cathepsin-D
    • Physiological/organismal consequences not addressed
  9. 2025 Medium

    Revealed cell-type context dependence by showing that in A549 cells GCC88 does not tether retromer/retriever-dependent carriers, which are instead handled by golgin-97/245.

    Evidence CRISPR/Cas9 knockout of retromer/retriever subunits with ETC redirection and cargo assays

    PMID:40439270

    Open questions at the time
    • Single lab, single cell line; partially contradicts earlier HeLa-based tethering data
    • Mechanistic basis of the cell-type difference unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identity of the GCC88 GRIP-domain membrane receptor and the carrier determinant recognized by its N-terminal capture motif remain unresolved, as does the functional significance of GCC88 phase separation.
  • No identified GRIP membrane receptor for GCC88
  • Coat/receptor recognized by the N-terminal capture motif unknown
  • Functional role of GCC88 condensate formation untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0005198 structural molecule activity 2
Localization
GO:0005794 Golgi apparatus 4 GO:0005886 plasma membrane 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9609507 Protein localization 2
Partners
ITSN1M6PRSTX6TGOLN2

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 The C-terminal GRIP domain (also called GLD) of GCC1p (GCC88) is sufficient for targeting to the Golgi apparatus in transfected mammalian cells, as demonstrated by GFP chimera experiments. Site-directed mutagenesis identified two conserved aromatic residues critical for the function of this Golgi-targeting domain. GFP chimera transfection, site-directed mutagenesis, fluorescence microscopy Current biology : CB High 10209125
2002 GCC88 is a peripheral membrane protein localized to the TGN of HeLa cells. Overexpression of full-length GCC88 leads to formation of large electron-dense structures extending from the trans-Golgi that contain syntaxin 6 and TGN38 but not cis-Golgi markers, implicating GCC88 in organization of a specific TGN subcompartment involved in membrane transport. The N-terminal domain of GCC88 is required for formation of these abnormal structures. Immunofluorescence, immunoelectron microscopy, overexpression with domain truncations The Journal of biological chemistry High 12446665
2002 Overexpression of GFP-TbGRIP (T. brucei GRIP domain) in COS cells displaced endogenous GCC1p from the Golgi apparatus, indicating that the trypanosomatid and mammalian GRIP sequences interact with similar membrane determinants. Overexpression competition assay, fluorescence microscopy European journal of cell biology Medium 12416725
2004 The GRIP domains of GCC88 and GCC185 differ in membrane binding properties from p230/golgin-245 and golgin-97: they do not interact with the Arf-like GTPase Arl1 in vivo. Overexpression of GCC88 and GCC185 produces distinct, non-overlapping TGN subcompartment structures, indicating that GCC88 is recruited to a functionally distinct TGN domain. Overexpression, immunofluorescence, immunoelectron microscopy, in vivo interaction assays Journal of cell science High 15522892
2005 GCC88 forms homodimers exclusively and does not form heterodimers with other GRIP domain proteins (p230, golgin-97, GCC185). Two-hybrid analysis showed that N- and C-terminal fragments of GCC88 interact with themselves but not each other, consistent with parallel coiled-coil homodimer formation. Co-immunoprecipitation of epitope-tagged proteins, chemical cross-linking, yeast two-hybrid The Biochemical journal High 15654769
2007 GCC88 defines a specific retrograde transport pathway from early endosomes to the TGN. siRNA depletion of GCC88 in HeLa cells blocks plasma membrane-TGN recycling of TGN38 and a CD8-mannose-6-phosphate receptor tail fusion protein, with cargo stalled in early endosomes. GCC88 depletion dramatically alters TGN localization of syntaxin 6, and the transport block is rescued by syntaxin 6 overexpression. Shiga toxin retrograde transport is unaffected by GCC88 depletion, defining a GCC88-dependent pathway distinct from the Shiga toxin pathway. siRNA knockdown, fluorescence microscopy, cargo recycling assays, rescue experiments with syntaxin 6 overexpression Molecular biology of the cell High 17914056
2017 A short 20-50 residue region at the extreme N-terminus of GCC88 is necessary and sufficient to capture endosome-to-Golgi transport carriers at an ectopic location. The capture motif of GCC88 is distinct from those of golgin-97 and golgin-245, suggesting GCC88 captures a different class of endosome-derived carriers by a different mechanism. Domain mapping with ectopic relocalization assay, minimal region identification BMC biology High 28122620
2018 Retromer-dependent retrograde trafficking of CI-M6PR from endosomes to TGN is selectively tethered by GCC88 but not golgin-97 or golgin-245. This GCC88-dependent retrograde pathway requires SNX3 but not SNX27 or SNX-BAR proteins. Vps35 knockout, cargo trafficking assays, endosome transport carrier tethering assays, genetic epistasis with SNX proteins The Journal of cell biology High 30559172
2018 GCC88 interacts with the long isoform of intersectin-1 (ITSN-1), a guanine nucleotide exchange factor for Cdc42, at the TGN. This interaction mediates actin-dependent dispersal of the Golgi ribbon involving non-muscle myosin IIA. Perturbation of Golgi morphology by silencing retromer subunit Vps26 or Tau overexpression is also dependent on the ITSN-1–GCC88 interaction. Co-immunoprecipitation, siRNA knockdown, actin inhibition, fluorescence microscopy, mass spectrometry identification of GCC88 interactors Molecular biology of the cell High 30540523
2019 Knockout of GCC88 perturbs retrieval of CI-M6PR from endosomes to TGN, decreases steady-state cellular levels of CI-M6PR, causes improper processing of cathepsin-D (a lysosomal hydrolase dependent on CI-M6PR for delivery to lysosomes), and reduces lysosomal proteolytic capacity, but does not impair autophagy efficiency. CRISPR/Cas9 knockout, cargo trafficking assays, cathepsin-D processing assay, lysosomal activity assay Cell biology international High 30791178
2020 Overexpression of GCC88 results in the formation of novel protein condensates in living cells, suggesting golgins including GCC88 have a propensity to phase-separate, potentially contributing to Golgi organization. Overexpression, fluorescence microscopy, FIB-SEM FEBS letters Medium 32668013
2021 Reduction of GCC1 (GCC88) decreases phosphorothioate antisense oligonucleotide (PS-ASO) activity without substantially affecting Golgi integrity, implicating GCC1 in endosomal release of PS-ASOs, consistent with its role in retrograde Golgi-endosome transport. siRNA knockdown, PS-ASO activity assay Nucleic acids research Medium 34244781
2025 In A549 cells, endosomal transport carriers dependent on retromer or retriever can be tethered by golgin-97 and golgin-245, but NOT by GCC88, indicating that in this cell line GCC88 does not serve as a tether for these ETCs. CRISPR/Cas9 knockout of retromer/retriever subunits, ETC redirection assay, cargo trafficking assay Cell biology international Medium 40439270
2025 GCC1 was used as a validated trans-Golgi network marker (alongside TGN46), and B4GAT1 (a dystroglycan-modifying enzyme) co-localizes with GCC1 but not GM130, indicating B4GAT1 resides in a Golgi subcompartment defined by GCC1. Fluorescent fusion protein expression, confocal microscopy co-localization with established compartment markers Glycobiology Low 40324206

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nature genetics 495 22158537
1999 A novel Golgi-localisation domain shared by a class of coiled-coil peripheral membrane proteins. Current biology : CB 130 10209125
2018 Retromer has a selective function in cargo sorting via endosome transport carriers. The Journal of cell biology 115 30559172
2002 GRIP domain-mediated targeting of two new coiled-coil proteins, GCC88 and GCC185, to subcompartments of the trans-Golgi network. The Journal of biological chemistry 110 12446665
2007 The golgin GCC88 is required for efficient retrograde transport of cargo from the early endosomes to the trans-Golgi network. Molecular biology of the cell 77 17914056
2004 Mammalian GRIP domain proteins differ in their membrane binding properties and are recruited to distinct domains of the TGN. Journal of cell science 65 15522892
2017 The golgin coiled-coil proteins capture different types of transport carriers via distinct N-terminal motifs. BMC biology 64 28122620
2002 Targeting of the GRIP domain to the trans-Golgi network is conserved from protists to animals. European journal of cell biology 40 12416725
2006 Transcriptional changes common to human cocaine, cannabis and phencyclidine abuse. PloS one 38 17205118
2018 Intersectin-1 interacts with the golgin GCC88 to couple the actin network and Golgi architecture. Molecular biology of the cell 33 30540523
2020 The golgin family exhibits a propensity to form condensates in living cells. FEBS letters 31 32668013
2005 The trans-Golgi network GRIP-domain proteins form alpha-helical homodimers. The Biochemical journal 29 15654769
2007 The intestinal guanylin system and seawater adaptation in eels. General and comparative endocrinology 23 17561018
2006 Identification of two functional guanylin receptors in eel: multiple hormone-receptor system for osmoregulation in fish intestine and kidney. General and comparative endocrinology 20 16753163
2001 Cloning and expression of two isoforms of guanylate cyclase C (GC-C) from the European eel (Anguilla anguilla). Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 19 11399493
2021 Regulation of mTORC1 activity by the Golgi apparatus. Faculty reviews 16 34195689
2022 Melanin Promotes Spore Production in the Rice Blast Fungus Magnaporthe oryzae. Frontiers in microbiology 12 35295315
2021 Golgi-58K can re-localize to late endosomes upon cellular uptake of PS-ASOs and facilitates endosomal release of ASOs. Nucleic acids research 12 34244781
2008 Guanylin-like peptides, guanylate cyclase and osmoregulation in the European eel (Anguilla anguilla). General and comparative endocrinology 10 19028495
2005 Enterotoxin/guanylin receptor type guanylyl cyclases in non-mammalian vertebrates. Zoological science 9 15930822
2021 Global 3'-untranslated region landscape mediated by alternative polyadenylation during meiotic maturation of pig oocytes. Reproduction in domestic animals = Zuchthygiene 8 34647356
2014 Genome-wide association study of medication adherence in chronic diseases in the korean population. Genomics & informatics 4 25317111
2023 Gcc1 homologs regulate growth, oxidative stress, conidiation and appressorium formation in Colletotrichum siamense and Colletotrichum graminicola. Microbial pathogenesis 2 37437644
2025 Systematic and comprehensive analysis of major localizations of alpha-dystroglycan-specific modifying enzymes. Glycobiology 1 40324206
2019 A role of GCC88 in the retrograde transport of CI-M6PR and the maintenance of lysosomal activity. Cell biology international 1 30791178
2025 Disruption of Retriever Function Impacts Retrograde Trafficking From Endosomes. Cell biology international 0 40439270

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