Human Molecular Genetics, Vol 6, 2205-2212, Copyright © 1997 by Oxford University Press
S Engelender, AH Sharp, V Colomer, MK Tokito, A Lanahan, P Worley, EL Holzbaur and CA Ross
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.
ARTICLES
Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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