Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Mar 20;10(3):1402-1410.
doi: 10.1021/acschemneuro.8b00448. Epub 2018 Nov 13.

C-Terminal CuII Coordination to α-Synuclein Enhances Aggregation

Dinendra L Abeyawardhane  1 , Denver R Heitger  1 , Ricardo D Fernández  1 , Ashley K Forney  1 , Heather R Lucas  1
Affiliations

C-Terminal CuII Coordination to α-Synuclein Enhances Aggregation

Dinendra L Abeyawardhane et al. ACS Chem Neurosci. .

Abstract

The structurally dynamic amyloidogenic protein α-synuclein (αS) is universally recognized as a key player in Parkinson's disease (PD). Copper, which acts as a neuronal signaling agent, is also an effector of αS structure, aggregation, and localization in vivo. In humans, αS is known to carry an acetyl group on the starting methionine residue, capping the N-terminal free amine which was a known high-affinity CuII binding site. We now report the first detailed characterization data using electron paramagnetic resonance (EPR) spectroscopy to describe the CuII coordination modes of N-terminally acetylated αS (NAcαS). Through use of EPR hyperfine structure analyses and the Peisach-Blumberg correlation, an N3O1 binding mode was established that involves the single histidine residue at position 50 and a lower population of a second CuII-binding mode that may involve a C-terminal contribution. We additionally generated an N-terminally acetylated disease-relevant variant, NAcH50Q, that promotes a shift in the CuII binding site to the C-terminus of the protein. Moreover, fibrillar NAcH50Q-CuII exhibits enhanced parallel β-sheet character and increased hydrophobic surface area compared to NAcαS-CuII and to both protein variants that lack a coordinated cupric ion. The results presented herein demonstrate the differential impact of distinct CuII binding sites within NAcαS, revealing that C-terminal CuII binding exacerbates the structural consequences of the H50Q missense mutation. Likewise, the global structural modifications that result from N-terminal capping augment the properties of CuII coordination. Hence, consideration of the effect of CuII on NAcαS and NAcH50Q misfolding may shed light on the extrinsic or environmental factors that influence PD pathology.

Keywords: EPR spectroscopy; N-Acetylated α-synuclein; Parkinson’s disease; aggregation; metal dyshomeostasis; missense mutation.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Publication types

LinkOut - more resources