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.
Highlights
IntroductionThe most common form of localised amyloid occurs in the aortic media (aortic medial amyloid; AMA) and is estimated to occur in 97% of Caucasian people above the age of 501
The most common form of localised amyloid occurs in the aortic media and is estimated to occur in 97% of Caucasian people above the age of 501
The QUARK and ROSETTA methods are broadly comparable in overall methodology, each assembling tertiary structures from structure fragments derived from the Protein Data Bank (PDB), but differ significantly in some aspects such as the fragment libraries, which are fixed in length 3- and 9-residues in ROSETTA but are variable in QUARK and in their scoring functions
Summary
The most common form of localised amyloid occurs in the aortic media (aortic medial amyloid; AMA) and is estimated to occur in 97% of Caucasian people above the age of 501. Molecular information about amyloid proteins in their monomeric, intermediate or fibrillar form and regarding their interaction and aggregation to form the insoluble fibrils is sparse. This is because amyloid proteins are notoriously difficult to study in their soluble forms due to their inherent propensity to aggregate along with the heterogeneous and transient nature of the key soluble intermediates. Short peptides composed only of these eight residues are capable of rapid aggregation into microcrystalline fibres[3,13] Removal of this C-terminal region from medin abolishes amyloid forming potential[14]. We use a combined experimental and computational approach to elucidate the early stages of medin nucleation, information that is critical for understanding of the initiation and progression of AMA and protein aggregation in general
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