ATROPHIN-1, THE DRPLA GENE-PRODUCT, INTERACTS WITH 2 FAMILIES OF WW DOMAIN-CONTAINING PROTEINS

Atrophin-1 contains a polyglutamine repeat, expansion of which is resp onsible for dentatorubral and pallidoluysian atrophy (DRPLA). The norm al function of atrophin-1 is unknown. We have identified five atrophin -1 interacting proteins (AIPs) which bind to atrophin-1 in the vicinit y of the polyglutamine tract using the yeast two-hybrid system. Four o f the interactions' were confirmed using in vitro binding assays. All five interactors contained multiple WW domains. Two are novel. The AIP s can be divided into two distinct classes. AIP1 and AIP3/WWP3 are MAG UK-like multidomain proteins containing a number of protein-protein in teraction modules, namely a guanylate kinaselike region, two WW domain s, and multiple PDZ domains. AIP2/WWP2, AIP4, and AIP5/WWP1 are highly homologous, each having four WW domains and a HECT domain characteris tic of ubiquitin ligases. These interactors are similar to recently is olated huntingtin-interacting proteins, suggesting possible commonalit y of function between two proteins responsible for very similar diseas es.