Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin.
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.
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
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
Hum. Mol. Genet.
Date: Dec. 01, 1997
PubMed ID: 9361024
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