THESIS
2015
xi, 45 pages : illustrations (some color) ; 30 cm
Abstract
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...[
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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.
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