title: Investigation of the early stages of human γD-crystallin aggregation process.
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 γD-crystallin (HγDC), 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 HγDC using molecular dynamics and molecular docking simulations. Our findings demonstrated that incubation of HγDC 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 β-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 HγDC that is important to the early stages of HγDC aggregation involved in cataractogenesis.
authors.affiliation: a Department of Chemical Engineering , National Taiwan University , Taipei 10617 , Taiwan.
authors.forename: Chih-Kai
authors.initials: CK
authors.lastname: Chang
authors.affiliation: a Department of Chemical Engineering , National Taiwan University , Taipei 10617 , Taiwan.
authors.forename: Steven S-S
authors.initials: SS
authors.lastname: Wang
authors.affiliation: a Department of Chemical Engineering , National Taiwan University , Taipei 10617 , Taiwan.
authors.forename: Chun-Hsien
authors.initials: CH
authors.lastname: Lo
authors.affiliation: a Department of Chemical Engineering , National Taiwan University , Taipei 10617 , Taiwan.
authors.forename: Hsiang-Chun
authors.initials: HC
authors.lastname: Hsiao
authors.affiliation: b Department of Optometry, Central Taiwan University of Science and Technology , Taichung 40601 , Taiwan.
authors.forename: Josephine W
authors.initials: JW
authors.lastname: Wu
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D055672:Static Electricity; D013329:Structure-Activity Relationship; D038222:gamma-Crystallins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D000682:Amyloid; C504903:CRYGD protein, human; D066329:Protein Aggregates; D038222:gamma-Crystallins
keywords: aggregation; cataract; crystallin; fibril; unfolding