The human myostatin precursor protein : structure, function and amyloid formation : implications for the muscle wastage disease sporadic inclusion body myositis : a dissertation presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry at Massey University, Palmerston North, New Zealand
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Date
2010
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Massey University
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Abstract
Myostatin is a major player in the regulation of mammalian muscle growth and
development, maintaining the balance between proliferation and differentiation prenatally
and the quiescence of satellite cells in adults. An absence or overexpression of
myostatin results in double-muscling and cachexia respectively, placing myostatin as
a promising target in the treatment of muscle wastage diseases.
As a transforming growth factor-β superfamily member, myostatin is produced as a
precursor protein, consisting of a propeptide region N-terminal to the growth factor
domain. Cleavage of the precursor between the domains forms the myostatin latent
complex, an inhibitory structure which is exported from the cell where a second
cleavage event releases the active myostatin growth factor. The precursor protein,
propeptide, and latent complex play important roles in the regulation of myostatin.
However, their structure and function are poorly understood, and a possible role for
the myostatin precursor protein in the muscle wastage disease sporadic inclusion body
myositis, suggests that pre-growth factor forms of myostatin may be additional
important therapeutic targets.
This thesis presents an investigation into the structure and function of the myostatin
precursor protein, the latent complex, and the propeptide region within these, with
comparisons to a mutant form of myostatin responsible for the naturally-occurring
double-muscled phenotype of the Piedmontese cattle breed. Results suggest that the
diverse functions of the propeptide region are facilitated by regions of intrinsic
disorder within a primarily structured domain, and that conformational alterations
accompany the precursor to latent complex transition, resulting in a tighter inhibitory
structure. Comparative analyses between the wild-type and mutant proteins suggest
that the Piedmontese phenotype is due to a reduced capacity for covalent dimerisation
and significant structural alterations within the type I receptor-binding domain.
Investigation into misfolded myostatin precursor protein found that the precursor is
able to form cytotoxic amyloid aggregates and mature fibrils under partially
denaturing conditions, suggesting a possible mechanism for the role of the myostatin
precursor in sporadic inclusion body myositis.
Together, these novel results contribute important information towards an
understanding of myostatin structure, function and regulation in both normal and
disease scenarios.
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Keywords
Myostatin precursor protein, Muscle wastage disease