Biophysical analysis of normal transthyretin: implications for fibril formation in senile systemic amyloidosis
Transthyretin (TTR) is a plasma protein that transports thyroid hormone and retinol binding protein-vitamin A complex. Eighty-four variants of TTR have been identified and seventy-four are associated with familial amyloidotic polyneuropathy. Normal TTR is the major protein found in the fibrillar deposits in the heart at time of autopsy of individuals with senile systemic amyloidosis. The mechanism by which normally soluble TTR deposits as organ-damaging, insoluble, pathological fibrils late in life is unknown. Understanding the mechanism of fibrillogenesis of normal TTR is critical to the design of clinical treatments aimed at retardation, prevention, or reversal of fibril deposition. We have employed a biophysical approach to explore the hypothesis that an instability in a particular secondary or tertiary structure plays a role in the ability of normal TTR to form fibrils at physiological pH. Using far UV circular dichroic (CD) spectroscopy as a function of temperature we have identified simultaneous, cooperative, reversible structural changes in the beta-sheet and alpha-helical regions. The flexible short, surface-located loops undergo an irreversible conformational change at a lower temperature. Spectra before and after heat...Continue Reading
Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications
Structure of prealbumin: secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 A
Alteration in molecular structure which results in disease: the Met-30 variant of human plasma transthyretin
Strjcture of human plasma prealbumin at 2-5 A resolution. A preliminary report on the polypeptide chain conformation, quaternary structure and thyroxine binding
The acid-mediated denaturation pathway of transthyretin yields a conformational intermediate that can self-assemble into amyloid
Guanidine hydrochloride-induced denaturation and refolding of transthyretin exhibits a marked hysteresis: equilibria with high kinetic barriers
Characterization of the transthyretin acid denaturation pathways by analytical ultracentrifugation: implications for wild-type, V30M, and L55P amyloid fibril formation
The structure of human retinol-binding protein (RBP) with its carrier protein transthyretin reveals an interaction with the carboxy terminus of RBP
The most pathogenic transthyretin variant, L55P, forms amyloid fibrils under acidic conditions and protofilaments under physiological conditions
The tetrameric protein transthyretin dissociates to a non-native monomer in solution. A novel model for amyloidogenesis.
Heating of proteins as a means of improving crystallization: a successful case study on a highly amyloidogenic triple mutant of human transthyretin
Structural insight into pH-induced conformational changes within the native human transthyretin tetramer
Why is Leu55-->Pro55 transthyretin variant the most amyloidogenic: insights from molecular dynamics simulations of transthyretin monomers
Stability and fibril formation properties of human and fish transthyretin, and of the Escherichia coli transthyretin-related protein
Transthyretin and familial amyloidotic polyneuropathy. Recent progress in understanding the molecular mechanism of neurodegeneration
Expression, purification, and in vitro cysteine-10 modification of native sequence recombinant human transthyretin
A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment.
Disulfide-bond formation in the transthyretin mutant Y114C prevents amyloid fibril formation in vivo and in vitro
Amyloid deposits around nerves can damage and disrupt smooth information processing between the brain and organs. Here is the latest research on amyloidosis-associated polyneuropathies.