Probing Medin Monomer Structure and its Amyloid Nucleation Using13C-Direct Detection NMR in Combination with Structural Bioinformatics.
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 and13C-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.
Institute of Integrative Biology, University of Liverpool, Biosciences Building, Crown Street, L69 7ZB, UK.
Hannah A
HA
Davies
Institute of Integrative Biology, University of Liverpool, Biosciences Building, Crown Street, L69 7ZB, UK.
Daniel J
DJ
Rigden
Institute of Integrative Biology, University of Liverpool, Biosciences Building, Crown Street, L69 7ZB, UK.
Marie M
MM
Phelan
Institute of Integrative Biology, University of Liverpool, Biosciences Building, Crown Street, L69 7ZB, UK.
Jillian
J
Madine
D000682:Amyloid / Q000737:chemistry*; D000954:Antigens, Surface / Q000737:chemistry*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D006801:Humans; D008894:Milk Proteins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation
D000682:Amyloid; D000954:Antigens, Surface; C098942:MFGE8 protein, human; D008894:Milk Proteins