Huntingtin-associated protein 1 (HAP1) interacts with the p150(Glued) subunit of dynactin

Simone Engelender, Alan H. Sharp, Veronica Colomer, Mariko K. Tokito, Anthony Lanahan, Paul Worley, Erika L.F. Holzbaur, Christopher A. Ross

Research output: Contribution to journalArticle

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine repeat in the HD protein huntingtin. Huntingtin's localization within the cell includes an association with cytoskeletal elements and vesicles. We previously identified a protein (HAP1) which binds to huntingtin in a glutamine repeat length-dependent manner. We now report that HAP1 interacts with cytoskeletal proteins, namely the p150(Glued) subunit of dynactin and the pericentriolar protein PCM-1. Structural predictions indicate that both HAP1 and the interacting proteins have a high probability of forming coiled coils. We examined the interaction of HAP1 with p150(Glued). Binding of HAP1 to p150(Glued) (amino acids 879-1150) was confirmed in vitro by binding of p150(Glued) to a HAP1-GST fusion protein immobilized on glutathione-Sepharose beads. Also, HAP1 co-immunoprecipitated with p150(Glued) from brain extracts, indicating that the interaction occurs in vivo. Like HAP1, p150(Glued) is highly expressed in neurons in brain and both proteins are enriched in a nerve terminal vesicle-rich fraction. Double label immunofluorescence experiments in NGF-treated PC12 cells using confocal microscopy revealed that HAP1 and p150(Glued) partially co-localize. These results suggest that HAP1 might function as an adaptor protein using coiled coils to mediate interactions among cytoskeletal, vesicular and motor proteins. Thus, HAP1 and huntingtin may play a role in vesicle trafficking within the cell and disruption of this function could contribute to the neuronal dysfunction and death seen in HD.

Original languageEnglish (US)
Pages (from-to)2205-2212
Number of pages8
JournalHuman molecular genetics
Volume6
Issue number13
StatePublished - Dec 1 1997

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Engelender, S., Sharp, A. H., Colomer, V., Tokito, M. K., Lanahan, A., Worley, P., Holzbaur, E. L. F., & Ross, C. A. (1997). Huntingtin-associated protein 1 (HAP1) interacts with the p150(Glued) subunit of dynactin. Human molecular genetics, 6(13), 2205-2212.