Novel Regulatory Mechanisms of Cytoplasmic Dynein

Cytoplasmic dynein is unique among cellular motors not only in its size and complexity but also its diversity of functions. It is essential for many mitotic and interphase transport processes and its misregulation or malfunction results in devastating neurological disorders. Over 20 years of research in the field has identified many recruitment and regulatory factors, with dynactin and NudE/L-Lis1 being the most ubiquitous and well described. Additionally we have recently gained detailed, high-resolution structures of the dynein motor domain and models for dynein stepping and mechanochemistry based on single molecule studies. Despite this progress, little is known about the structure and coordination of functions at the base of the dynein complex, where nearly all interactions with regulatory and recruitment proteins occur. The studies herein examine two mechanisms of regulation that occur through dynein's base. First we probe the contribution of the light chains to dynein function, structure and interaction with regulators. Second we identify a novel mechanism by which dynactin increases dynein run length solely via interactions with the intermediate chain. These findings represent the new frontier in the dynein field as investigators increasingly recognize the importance of long-range dynein regulatory mechanisms.