Investigation of the early stages of human £^D-crystallin aggregation process
Journal
Journal of Biomolecular Structure and Dynamics
Journal Volume
35
Journal Issue
5
Pages
1042-1054
Date Issued
2017
Author(s)
Abstract
Cataract, a major cause of visual impairment worldwide, is a common disease of the eye lens related to protein aggregation. Several factors including the exposure of ultraviolet irradiation and possibly acidic condition may induce the unfolding and subsequent aggregation of the crystallin proteins leading to crystalline lens opacification. Human £^D-crystallin (H£^DC), a 173 residue monomeric protein, abundant in the nucleus of the human eye lens, has been shown to aggregate and form amyloid fibrils under acidic conditions and that this aggregation route is thought to be a potential initiation pathway for the onset of age-related nuclear cataract. However, the underlying mechanism of fibril formation remains elusive. This report is aimed at examining the structural changes and possible amyloid fibril formation pathway of H£^DC using molecular dynamics and molecular docking simulations. Our findings demonstrated that incubation of H£^DC under the acidic condition redistributes the protein surface charges and affects the protein interaction with its surrounding solvent environment. This brings about a twist motion in the overall tertiary structure that gives rise to newly formed anti-parallel £]-strands in the C-terminal flexible loop regions. The change in protein structural conformation also involves an alteration in specific salt-bridge interactions. Altogether, these findings revealed a plausible mechanism for amyloid fibril formation of H£^DC that is important to the early stages of H£^DC aggregation involved in cataractogenesis. ? 2016 Informa UK Limited, trading as Taylor & Francis Group.
Subjects
aggregation
cataract
crystallin
fibril
unfolding
SDGs
Other Subjects
gamma crystallin; amino acid; amyloid; CRYGD protein, human; gamma crystallin; protein aggregate; protein binding; Article; beta sheet; conformational transition; controlled study; crystal structure; molecular docking; molecular dynamics; molecular interaction; pH measurement; protein aggregation; protein domain; protein interaction; protein tertiary structure; structure analysis; surface charge; binding site; chemistry; human; hydrogen bond; metabolism; molecular model; pH; protein conformation; protein stability; proteinosis; static electricity; structure activity relation; Amino Acids; Amyloid; Binding Sites; gamma-Crystallins; Humans; Hydrogen Bonding; Hydrogen-Ion Concentration; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Aggregates; Protein Aggregation, Pathological; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Protein Stability; Static Electricity; Structure-Activity Relationship
Type
journal article