No abstract

We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin. Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it. Deletion of the gene encoding a prefoldin subunit in S. cerevisiae results in a phenotype similar to those found when c-cpn is mutated, namely impaired functions of the actin and tubulin-based cytoskeleton. Consistent with prefoldin having a general role in chaperonin-mediated folding, we identify homologs in archaea, which have a class II chaperonin but contain neither actin nor tubulin. We show that by directing target proteins to chaperonin, prefoldin promotes folding in an environment in which there are many competing pathways for nonnative proteins.

The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple disease-causing missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C. We find a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus implicated in unexplained MCD. The mutations in KIF5C, KIF2A and DYNC1H1 drastically affect ATP hydrolysis, productive protein folding or microtubule binding, while suppression of Tubg1 expression in vivo interferes with proper neuronal migration and expression of Tubg1 mutations in S. cerevisiae results in disruption of normal microtubule behaviour. Our data reinforce the importance of centrosome- and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and post-mitotic processes are major contributors to the pathogenesis of MCD.