Probing Medin Monomer Structure and its Amyloid Nucleation Using 13C-Direct Detection NMR in Combination with Structural Bioinformatics



Davies, HA, Rigden, DJ ORCID: 0000-0002-7565-8937, Phelan, MM and Madine, J ORCID: 0000-0001-9963-5871
(2017) Probing Medin Monomer Structure and its Amyloid Nucleation Using 13C-Direct Detection NMR in Combination with Structural Bioinformatics. Scientific Reports, 7.

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Abstract

Aortic medial amyloid is the most prevalent amyloid found to date, but remarkably little is known about it. It is characterised by aberrant deposition of a 5.4 kDa protein called medin within the medial layer of large arteries. Here we employ a combined approach of ab initio protein modelling and 13C-direct detection NMR to generate a model for soluble monomeric medin comprising a stable core of three β-strands and shorter more labile strands at the termini. Molecular dynamics simulations suggested that detachment of the short, C-terminal β-strand from the soluble fold exposes key amyloidogenic regions as a potential site of nucleation enabling dimerisation and subsequent fibril formation. This mechanism resembles models proposed for several other amyloidogenic proteins suggesting that despite variations in sequence and protomer structure these proteins may share a common pathway for amyloid nucleation and subsequent protofibril and fibril formation.

Item Type: Article
Uncontrolled Keywords: Protein aggregation, Protein structure predictions, Solution-state NMR
Depositing User: Symplectic Admin
Date Deposited: 23 Mar 2017 10:57
Last Modified: 02 Sep 2021 14:10
DOI: 10.1038/srep45224
Open Access URL: http://www.nature.com/articles/srep45224
URI: https://livrepository.liverpool.ac.uk/id/eprint/3006586