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Investigating the pernicious effects of heparan sulfate in serum amyloid A1 protein aggregation: a structural bioinformatics approach
G. Chandrasekhar,
Published in Taylor and Francis Ltd.
Amyloid-A mediated (AA) amyloidosis is the pathogenic byproduct of body’s prolonged exposure to inflammatory conditions. It is described by the aggregation of mutated/misfolded serum amyloid A1 (SAA1) protein in various tissues and organs. Genetic polymorphism G90D is suspected to cause AA amyloidosis, although the causal mechanism remains cryptic. Recent experimental findings insinuate that heparan sulphate (HS), a glycosaminoglycans, exhibits binding with SAA1 to promote its aggregation. To foster the enhanced binding of HS, we computationally determined the pernicious modifications in G90D mutant SAA1 protein. Also, we examined the influence of HS on the dynamic conformation of mutant SAA1 that could potentially succor amyloidosis. Accordingly, the protein-ligand binding studies indicate that upon SNP G90D, SAA1 protein exhibited an augmented association with HS. Further, the simulation of HS bound mutant SAA1 complex delineates an increase in RMSD, Rg, and RMSF. Also, both RMSD and Rg evinced a fluctuating trajectory. Further, the complex showed increase of beta turn in its secondary structural composition. Additionally, the free energy landscape of mutant SAA1-HS complex posits the occurrence of multiple global minima conformers as opposed to the presence of a single global energy minima conformation in native SAA1 protein. In conclusion, the aforementioned conformational ramifications induced by HS on SAA1 could potentially be the proteopathic incendiary behind AA amyloidosis; this incendiary will need to be considered in future studies for developing effective therapeutics against AA amyloidosis. Communicated by Ramaswamy H. Sarma. © 2020 Informa UK Limited, trading as Taylor & Francis Group.
About the journal
JournalData powered by TypesetJournal of Biomolecular Structure and Dynamics
PublisherData powered by TypesetTaylor and Francis Ltd.