N‐terminal acetylation of α‐synuclein induces increased transient helical propensity and decreased aggregation rates in the intrinsically disordered monomer

Citations Over TimeTop 10% of 2012 papers

Abstract

The conformational properties of soluble α-synuclein, the primary protein found in patients with Parkinson's disease, are thought to play a key role in the structural transition to amyloid fibrils. In this work, we report that recombinant 100% N-terminal acetylated α-synuclein purified under mild physiological conditions presents as a primarily monomeric protein, and that the N-terminal acetyl group affects the transient secondary structure and fibril assembly rates of the protein. Residue-specific NMR chemical shift analysis indicates substantial increase in transient helical propensity in the first 9 N-terminal residues, as well as smaller long-range changes in residues 28-31, 43-46, and 50-66: regions in which the three familial mutations currently known to be causative of early onset disease are found. In addition, we show that the N-terminal acetylated protein forms fibrils that are morphologically similar to those formed from nonacetylated α-synuclein, but that their growth rates are slower. Our results highlight that N-terminal acetylation does not form significant numbers of dimers, tetramers, or higher molecular weight species, but does alter the conformational distributions of monomeric α-synuclein species in regions known to be important in metal binding, in association with membranes, and in regions known to affect fibril formation rates.

Related Papers

• → Microtubules are acetylated in domains that turn over slowly(1989)263 cited
• → Interplay between p300 and HDAC1 regulate acetylation and stability of Api5 to regulate cell proliferation(2021)7 cited
• → IDPsBind: a repository of binding sites for intrinsically disordered proteins complexes with known 3D structures(2022)3 cited
• → Intrinsically Disordered Proteins (IDPs)(2022)1 cited
• → Interplay between p300 and HDAC1 regulate acetylation and stability of Api5 to regulate cell proliferation(2020)1 cited