HUNTINGTIN-ASSOCIATED PROTEIN-1 (HAP1) BINDS TO A TRIO-LIKE POLYPEPTIDE, WITH A RAD GUANINE-NUCLEOTIDE EXCHANGE FACTOR DOMAIN

Huntington's disease (HD) occurs when the widely expressed protein hun tingtin contains an expanded glutamine repeat, The selective degenerat ion and neuronal morphologic abnormalities of HD may involve interacti ons with proteins that bind to huntingtin, such as HAP1, The biologica l significance of this interaction is unclear because neither HAP1 nor huntingtin have significant homology to known proteins, Therefore, we sought to identify HAP1-binding proteins, using the yeast two-hybrid system, we isolated a rat cDNA encoding part of a protein that interac ts with HAP1, and we confirmed the specificity of this interaction usi ng an in vitro protein-binding assay, We called the protein Duo becaus e it is closely related to the human protein Trio but Is shorter, Nort hern blot analysis indicates brain-specific expression of Due. Human D uo contains a guanine nucleotide exchange factor (GEF) domain that is likely to be rad-specific, a pleckstrin homology (PH) domain and spect rin-like repeat units, These data support the hypothesis that huntingt in is involved in vesicle trafficking and cytoskeletal functions, and raise the possibility of a role for huntingtin in the regulation of a ras-related signaling pathway.