In silico prediction of novel residues involved in amyloid primary nucleation of human I56T and D67H lysozyme

BMC Structural Biology
Jeddidiah W D Griffin, Patrick C Bradshaw

Abstract

Amyloidogenic proteins are most often associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, but there are more than two dozen human proteins known to form amyloid fibrils associated with disease. Lysozyme is an antimicrobial protein that is used as a general model to study amyloid fibril formation. Studies aimed at elucidating the process of amyloid formation of lysozyme tend to focus on partial unfolding of the native state due to the relative instability of mutant amyloidogenic variants. While this is well supported, the data presented here suggest the native structure of the variants may also play a role in primary nucleation. Three-dimensional structural analysis identified lysozyme residues 21, 62, 104, and 122 as displaced in both amyloidogenic variants compared to wild type lysozyme. Residue interaction network (RIN) analysis found greater clustering of residues 112-117 in amyloidogenic variants of lysozyme compared to wild type. An analysis of the most energetically favored predicted dimers and trimers provided further evidence for a role for residues 21, 62, 104, 122, and 112-117 in amyloid formation. This study used lysozyme as a model to demonstrate the...Continue Reading

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Citations

Nov 30, 2018·PLoS Computational Biology·Brandon M ButlerS Banu Ozkan
May 25, 2020·Protoplasma·Nimisha GuptaSaima Wajid
Dec 10, 2020·Computational and Mathematical Methods in Medicine·Yanjuan LiXiaoyan Liu

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Methods Mentioned

BETA
sequence-based predictions

Software Mentioned

Multialign Viewer
ClusPro
MCODE
MatchMaker
Aggrescan
TANGO
Cytoscape
RING
UCSF Chimera
Protein Graph Converter

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