Could have a dual role in dynein targeting and in ACTR1A/Arp1 subunit of dynactin pointed-end capping. Could be involved in ACTR1A pointed-end binding and in additional roles in linking dynein and dynactin to the cortical cytoskeleton. (updated: March 4, 2015)
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
No sequence conservation computed yet.
Total structural coverage: 12%
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The reference OMIM entry for this protein is 614758
Dynactin 4; dctn4
Dyn4
Dynactin, 62-kd subunit
P62
DESCRIPTION
DCTN4 is a subunit of the 20S dynactin complex. The dynactin complex is involved in microtubule-dependent vesicular transport, spindle assembly, and cell division (summary by Karki et al., 2000).
CLONING
By gene dosage analysis and sequencing candidate genes in a YAC contig covering the critical region of the 5q deletion syndrome (
153550), followed by database analysis, Boultwood et al. (2000) identified a DCTN4 clone designated 605d01. Northern blot analysis detected a 7.5-kb DCTN4 transcript in all 15 human tissues examined. By mass spectrometric analysis of the 62-kD protein that affinity purified with human dynactin, followed by EST database analysis and PCR of an NT2 human teratocarcinoma cDNA library, Karki et al. (2000) cloned DCTN4, which they called p62. The deduced 460-amino acid protein has a calculated molecular mass of 52.3 kD. It has an N-terminal domain with 11 cysteines, the last 8 of which fit the consensus sequence for a RING domain predicted to bind 2 Zn(2+) atoms. Northern blot analysis detected variable expression of an approximately 4.2-kb transcript in all tissues examined, with highest expression in heart and skeletal muscle. Immunocytochemical analysis revealed that p62 had a punctate cytoplasmic distribution as well as a centrosomal distribution typical of dynactin. By immunohistochemical analysis, Ayalon et al. (2008) showed that Dyn4 colocalized with other dynactin subunits in adult mouse muscle fibers. Dyn4 localized in a punctate distribution along costamere lines.
GENE FUNCTION
Karki et al. (2000) stated that p62 is present in the dynactin complex at a stoichiometry of 1 copy per complex and that it localizes at 1 end of the central ARP1 (ACTR1A;
605143) polymeric filament. Using biochemical and immunoprecipitation analyses, they showed that p62 associated with the rat 20S dynactin complex. Recombinant human p62 bound immobilized in vitro-translated human ARP1. Overexpression of p62 in PtK2 porcine kidney cells did not disrupt microtubule organization or the integrity of the Golgi, but it resulted in some p62 nuclear localization. ATP7B (
606882) localizes to the trans-Golgi network, where it transports copper to apoceruloplasmin (CP;
117700). When copper levels are in excess, ATP7B redistributes to a vesicular compartment near the biliary canalicular membranes, where excess copper is eliminated into bile. Using a yeast 2-hybrid screen of a human liver cDNA library, Lim et al. (2006) found that the N-terminal domain of ATP7B, which contains 6 N-terminal metal-binding sites, interacted with the C-terminal domain of p62. Coimmunoprecipitation analysis revealed that ATP7B, but not ATP7A (
300011), interacted with endogenous p62 in a human fibroblast line. Depletion of copper reduced interaction of ATP7B with p62. Mutation analysis revealed that the metal-binding CxxC motifs of ATP7B were required for its interaction with p62, predominantly CxxC motifs 4 through 6. Lim et al. (2006) concluded that ATP7B is transported along liver cell microtubules in a copper-dependent manner via interaction with p62. By yeast 2-hybrid analysis of a mouse heart cDNA library, Ayalon et al. (2008) found that Ankb (ANK2;
106410) interacted with Dyn4. Protein pull-down assays confirmed the interaction. Depletion of Ankb in adult mouse skeletal muscle fibers disrupted costamere-associated microtubules, concomitant with loss of costamere-associated Dyn4 expression.
MAPPING
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Subscribe to this protein entry history
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 614758 was added.