Metalloprotease-disintegrins are a family of transmembrane glycoproteins that have a role in fertilization, sperm migration, myoblast fusion, neural development and ectodomain shedding. In the present study we used the yeast two-hybrid system to search for proteins that interact with the cytoplasmic domain of two metalloprotease-disintegrins, tumour necrosis factor α convertase (TACE; ADAM17) and MDC9 (ADAM9; meltrin γ). We have identified mitotic arrest deficient 2 (MAD2) as a binding partner of the TACE cytoplasmic domain, and a novel MAD2-related protein, MAD2β, as a binding partner of the MDC9 cytoplasmic domain. MAD2β has 23% sequence identity with MAD2, which is a component of the spindle assembly (or mitotic) checkpoint mechanism. Northern blot analysis of human tissues indicates that MAD2β mRNA is expressed ubiquitously. The interaction of the TACE and MDC9 cytoplasmic domains with their binding partners has been confirmed biochemically. The independent identification of MAD2 and MAD2β as potential interacting partners of distinct metalloprotease-disintegrins raises the possibility of a link between metalloprotease-disintegrins and the cell cycle, or of functions for MAD2 and MAD2β that are not related to cell cycle control.