Class V myosins, coded by myosin 5, are the most studied and the proto-type unconventional myosins and are known to be involved in numerous cellular events such as organelle transports and tethering cellular compartments to actin filaments. Complete null mutation of myosin Va is lethal and mild missense mutations are known to cause the hereditary neurological disease known as the Griscelli syndrome and microvillus inclusion disease in humans. Previous study also showed the very C-terminal globular tail domain (GTD) of myosin V is responsible for binding to numerous cargos with diverse amino acid sequences and broad physiological functions. However, lack of structure information makes it hard to understand the detailed mechanism governing the cargo recognitions as well as diseas...[ Read more ]

Class V myosins, coded by myosin 5, are the most studied and the proto-type unconventional myosins and are known to be involved in numerous cellular events such as organelle transports and tethering cellular compartments to actin filaments. Complete null mutation of myosin Va is lethal and mild missense mutations are known to cause the hereditary neurological disease known as the Griscelli syndrome and microvillus inclusion disease in humans. Previous study also showed the very C-terminal globular tail domain (GTD) of myosin V is responsible for binding to numerous cargos with diverse amino acid sequences and broad physiological functions. However, lack of structure information makes it hard to understand the detailed mechanism governing the cargo recognitions as well as diseases caused by mutations in the motor.

In this thesis work, I collaborated with my colleagues and solved the crystal structures of myosinVa-GTD in its apo-form as well as in complex with two distinct cargos, melanophilin and Rab interacting lysosomal protein-like 2. The structure of the apo-form myosinVa-GTD indicate that the majority of identified frame-shirt, nonsense, or missense mutations in GTD are expected to alter its structure thereby impair the proper functions of myosin V. The structure of the GTD/cargo complex, together with detailed biochemical analyses, reveals the cargo-binding specificities of various isoforms of mammalian myosin V as well as very different cargo recognition mechanisms of myosin V from yeast and from higher eukaryotes.