Release of Long-range Tertiary Interactions Potentiates Aggregation of Natively Unstructured Alpha-synuclein

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2005 Jan 27

PMID 15671169

Citations 342

Authors

Carlos W Bertoncini

Young-Sang Jung

Claudio O Fernandez

Wolfgang Hoyer

Christian Griesinger

Thomas M Jovin

Markus Zweckstetter

Affiliations

Soon will be listed here.

Abstract

In idiopathic Parkinson's disease, intracytoplasmic neuronal inclusions (Lewy bodies) containing aggregates of the protein alpha-synuclein (alphaS) are deposited in the pigmented nuclei of the brainstem. The mechanisms underlying the structural transition of innocuous, presumably natively unfolded, alphaS to neurotoxic forms are largely unknown. Using paramagnetic relaxation enhancement and NMR dipolar couplings, we show that monomeric alphaS assumes conformations that are stabilized by long-range interactions and act to inhibit oligomerization and aggregation. The autoinhibitory conformations fluctuate in the range of nanoseconds to micro-seconds corresponding to the time scale of secondary structure formation during folding. Polyamine binding and/or temperature increase, conditions that induce aggregation in vitro, release this inherent tertiary structure, leading to a completely unfolded conformation that associates readily. Stabilization of the native, autoinhibitory structure of alphaS constitutes a potential strategy for reducing or inhibiting oligomerization and aggregation in Parkinson's disease.

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