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CLATHRIN INTERACTOR 1; CLINT1

CLATHRIN INTERACTOR 1; CLINT1

Alternative titles; symbolsEPSIN 4; EPN4EPSIN-RELATED PROTEIN; EPNRENTHOPROTINKIAA0171HGNC Approved Gene Symbol: CLINT1Cytogenetic location: 5q33.3 Genomic c...

Alternative titles; symbols

  • EPSIN 4; EPN4
  • EPSIN-RELATED PROTEIN; EPNR
  • ENTHOPROTIN
  • KIAA0171

HGNC Approved Gene Symbol: CLINT1

Cytogenetic location: 5q33.3 Genomic coordinates (GRCh38): 5:157,785,746-157,859,144 (from NCBI)

▼ TEXT

For background information on epsins, see EPN1 (607262).

▼ Cloning and Expression

Nagase et al. (1996) isolated a cDNA encoding EPN4, which they designated KIAA0171, from the immature myeloid cell line KG-1. The deduced protein contains 625 amino acids. Northern blot analysis revealed moderate expression in all tissues tested, with highest expression in skeletal muscle.

Wasiak et al. (2002) identified rat Epn4, which they called enthoprotin, by subcellular proteomics of clathrin-coated vesicles (CCVs). Epn4 was highly enriched on CCVs isolated from rat brain and liver extracts. By sequence analysis of tryptic peptides, they identified an epsin N-terminal homology (ENTH) domain and a consensus type-2 clathrin box in the C-terminal domain. The predicted molecular mass is about 68 kD, and Epn4 expressed by transfected COS-7 cells showed an apparent molecular mass of about 80 kD. Endogenous Epn4 localized in COS-7 cells in a punctate pattern that was enriched in a perinuclear pool that colocalized with clathrin (118955) and with the clathrin adaptor protein complex AP1 (see 607291).

▼ Gene Function

Using pull-down assays, Wasiak et al. (2002) found that rat Epn4 interacts with AP1, AP2, clathrin, and GGA2 (606005). They determined that, through its C-terminal domain, Epn4 binds to the terminal domain of the clathrin heavy chain and stimulates clathrin assembly.

Saint-Pol et al. (2004) found that HeLa cell EPN4 was involved in retrograde transport of endogenous cargo proteins and bacterial Shiga toxin from early and recycling endosomes to the trans-Golgi network.

▼ Mapping

By radiation hybrid analysis, Nagase et al. (1996) mapped the EPN4 gene to chromosome 5.

▼ Molecular Genetics

Pimm et al. (2005) investigated 450 unrelated white English, Irish, Welsh, and Scottish research subjects with schizophrenia and 450 ancestrally matched supernormal controls. Four adjacent markers at the 5-prime end of the EPN4 gene showed significant evidence of linkage disequilibrium with schizophrenia. These included included 2 microsatellite markers and 2 SNPs within the EPN4 gene. A series of different 2- and 3-marker haplotypes were also significantly associated with schizophrenia. Since the EPN4 gene encodes enthoprotin, which has a role in transport and stability of neurotransmitter vesicles at the synapses and within neurons, they considered it likely that a genetically determined abnormality in the structure, function, or expression of this protein is responsible for genetic susceptibility to a subtype of schizophrenia on 5q33.3 (SCZD1; 181510).

▼ Biochemical Features

Crystal Structure

Miller et al. (2007) characterized the molecular details governing the sorting of a SNARE into clathrin-coated vesicles, namely, the direct recognition of the 3-helical bundle H(abc) domain of the mouse SNARE Vti1b (603207) by the human clathrin adaptor epsinR (EPNR, also known as CLINT1). Structures of each domain and of their complex showed that this interaction (dissociation constant 22 microM) is mediated by surface patches composed of approximately 15 residues each, the topographies of which are dependent on each domain's overall fold. Disruption of the interface with point mutations abolished the interaction in vitro and caused Vti1b to become relocalized to late endosomes and lysosomes. Miller et al. (2007) stated that this new class of highly specific, surface-surface interaction between the clathrin coat component and the cargo is distinct from the widely observed binding of short, linear cargo motifs by the assembly polypeptide (AP) complex and GGA adaptors and is therefore not vulnerable to competition from standard motif-containing cargoes for incorporation into clathrin-coated vesicles. Miller et al. (2007) proposed that conceptually similar but mechanistically different interactions direct the post-Golgi trafficking of many SNAREs.

Tags: 5q33.3