ISSN: 2161-0460

Journal of Alzheimers Disease & Parkinsonism
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  • Research Article   
  • J Alzheimers Dis Parkinsonism 2017, Vol 7(5): 378
  • DOI: 10.4172/2161-0460.1000378

Computational Analysis of Cholesterol Binding and Pore-Lining Regions in Alpha-Synuclein: Role in Mitochondrial Function

Gene A Morrill*, Adele B Kostellow and Raj K Gupta
Department of Physiology and Biophysics, Albert Einstein College of Medicine Bronx, , New York 10461, USA
*Corresponding Author : Gene A Morrill, Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York, USA, Tel: 718 430 2072, Email: gene.morrill@einstein.yu.edu

Received Date: Sep 12, 2017 / Accepted Date: Sep 19, 2017 / Published Date: Sep 26, 2017

Abstract

Alpha-synuclein (α-syn) protein is the major component of Lewy bodies, which are characteristic pathological trademarks for neurodegenerative diseases (e.g. Parkinson’s and Alzheimer’s diseases). It is primarily expressed in neural tissue, with smaller amounts found in heart, muscle and other tissues. The canonical form found in Homo sapiens (α-syn-1) contains 140 residues and interacts with neuronal mitochondria via an N-terminal 32 residue mitochondrial-targeting signal. All isoforms (there are 3) have multiple highly conserved lipid binding (KTKE(Q)G(Q) V) motifs, thought to mediate binding to phospholipid membranes. Two isoforms also contain an EF-hand-like (helixloop- helix) sequence found in a large family of calcium-binding proteins, as well as three copper binding sites. We investigate protein topology using computational analysis and find that each isoform contains a pore-lining region, two cholesterol-binding (CRAC/CARC) and three or four lipid binding motifs, with one cholesterol motif overlapping the pore-lining region. Two lipid-binding motifs also overlap the N-terminal mitochondrial-targeting region consistent with evidence that α-syn inserts into mitochondrial inner membrane. α-Syn-1 reportedly occurs physiologically as a helically folded tetramer that requires N-terminal acetylation. Thus, each α-syn-1 tetramer could contain 4 mitochondrial targeting regions, up to 4 pore-lining regions, 4 EF-hand domains, 8 bound cholesterol molecules and 16 lipid binding motifs with pore-lining regions merging to form a membrane channel. Cholesterol binding to CRAC motifs may in turn facilitate protein folding, Ca2+-channel formation, as well as mitochondrial membrane lipid-protein interactions, altering mitochondrial bioenergetics. Disruption of mitochondrial bioenergetics may be involved in the pathogenesis of Alzheimer’s disease and Parkinsonism.

Keywords: Alpha-synuclein; Pore-lining regions; Mitochondrial targeting regions; Cholesterol-binding (CRAC/CARC) motifs; KTKEGV motifs; EF-hand domains; Copper binding sites

Citation: Morrill GA, Kostellow AB, Gupta RK (2017) Computational Analysis of Cholesterol Binding and Pore-Lining Regions in Alpha-Synuclein: Role in Mitochondrial Function. J Alzheimers Dis Parkinsonism 7: 378. Doi: 10.4172/2161-0460.1000378

Copyright: © 2017 Morrill GA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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