Amyloidogenic Potential of Plaque and Thrombus Proteomes and of Fold-Switching Metamorphic Proteins

In previous work we have used the computer program AmyloGram to assess the amyloidogenic potential of proteins observed using mass spectrometry-based proteomics in thrombi extracted from individuals who had suffered an ischaemic stroke. As anticipated from our experimental observation of substantial amounts of amyloid in such clots, the AmyloGram scores were very high and entirely consistent with the amyloid nature of such thrombi. We here apply a similar strategy to assess the amyloidogenic nature of proteins in thrombi removed from venous thromboembolisms including pulmonary embolisms, similarly finding very high AmyloGram scores. The same is true for atherosclerotic plaques as determined from multiple studies in which the data were readily available. Amyloidogenesis is a specific activity or subset of a class of proteins known to adopt very different macrostates, in which amyloidogenesis to create insoluble fibrils is more or less irreversible. Another subset of multi-state proteins, whose conformational interchanges are much more reversible, involves what are referred to as ‘fold-switching’ or ‘metamorphic’ proteins’. We here use AmyloGram to analyse the amyloidogenic potential of these too, finding that while some are highly amyloidogenic their amyloidogenic potential is considerably more heterogeneous and little different from that of the overall proteome within Uniprot.