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Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin.

Human molecular genetics | Dec 18, 1997

http://www.ncbi.nlm.nih.gov/pubmed/9361024

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.

Pubmed ID: 9361024 RIS Download

Mesh terms: Animals | Autoantigens | Base Sequence | Brain Chemistry | Carbon-Oxygen Lyases | Cell Cycle Proteins | Cell Line | Chromatography, Affinity | Cytoskeleton | DNA, Complementary | DNA-(Apurinic or Apyrimidinic Site) Lyase | Humans | Kinesin | Macromolecular Substances | Microscopy, Confocal | Microtubule-Associated Proteins | Molecular Sequence Data | Nuclear Proteins | PC12 Cells | Protein Binding | Protein Conformation | Rats | Recombinant Fusion Proteins | Saccharomyces cerevisiae

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Associated grants

  • Agency: NIGMS NIH HHS, Id: GM48661
  • Agency: NIMH NIH HHS, Id: MH01152
  • Agency: NINDS NIH HHS, Id: NS16375

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