The loss of inhibitory C-terminal conformations in disease associated P123H β-synuclein

Protein Science : a Publication of the Protein Society
Maria K Janowska, Jean Baum

Abstract

β-synuclein (βS) is a homologue of α-synuclein (αS), the major protein component of Lewy bodies in patients with Parkinson's disease. In contrast to αS, βS does not form fibrils, mitigates αS toxicity in vivo and inhibits αS fibril formation in vitro. Previously a missense mutation of βS, P123H, was identified in patients with Dementia with Lewy Body disease. The single P123H mutation at the C-terminus of βS is able to convert βS from a nontoxic to a toxic protein that is also able to accelerate formation of inclusions when it is in the presence of αS in vivo. To elucidate the molecular mechanisms of these processes, we compare the conformational properties of the monomer forms of αS, βS and P123H-βS, and the effects on fibril formation of coincubation of αS with βS, and with P123H-βS. NMR residual dipolar couplings and secondary structure propensities show that the P123H mutation of βS renders it more flexible C-terminal to the mutation site and more αS-like. In vitro Thioflavin T fluorescence experiments show that P123H-βS accelerates αS fibril formation upon coincubation, as opposed to wild type βS that acts as an inhibitor of αS aggregation. When P123H-βS becomes more αS-like it is unable to perform the protective function ...Continue Reading

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May 16, 2017·Archives of Biochemistry and Biophysics·Eric B GibbsScott A Showalter
Nov 29, 2016·The European Journal of Neuroscience·Natalie LandeckDeniz Kirik
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Dec 12, 2018·The Journal of Physical Chemistry. B·Erik C CookScott A Showalter

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