Formation of the VHL-elongin BC tumor suppressor complex is mediated by the chaperonin TRiC

von Hippel-Lindau (VHL) disease is caused by loss of function of the VHL tu mor suppressor protein. Here, we demonstrate that the folding and assembly of VHL into a complex with its partner proteins, elongin B and elongin C (h erein, elongin BC), is directly mediated by the chaperonin TRiC/CCT. Associ ation of VHL with TRiC is required for formation of the VHL-elongin BC comp lex. A 55-amino acid domain of VHL is both necessary and sufficient for bin ding to TRiC. importantly, mutation or deletion of this domain is associate d with VHL disease. We identified two mutations that disrupt the normal int eraction with TRiC and impair VHL folding. Our results define a novel role for TRiC in mediating oligomerization and suggest that inactivating mutatio ns can impair polypeptide function by interfering with chaperone-mediated f olding.