title: Aggregation of γ-crystallins associated with human cataracts via domain swapping at the C-terminal β-strands.
abstract: The prevalent eye disease age-onset cataract is associated with aggregation of human γD-crystallins, one of the longest-lived proteins. Identification of the γ-crystallin precursors to aggregates is crucial for developing strategies to prevent and reverse cataract. Our microseconds of atomistic molecular dynamics simulations uncover the molecular structure of the experimentally detected aggregation-prone folding intermediate species of monomeric native γD-crystallin with a largely folded C-terminal domain and a mostly unfolded N-terminal domain. About 30 residues including a, b, and c strands from the Greek Key motif 4 of the C-terminal domain experience strong solvent exposure of hydrophobic residues as well as partial unstructuring upon N-terminal domain unfolding. Those strands comprise the domain-domain interface crucial for unusually high stability of γD-crystallin. We further simulate the intermolecular linkage of these monomeric aggregation precursors, which reveals domain-swapped dimeric structures. In the simulated dimeric structures, the N-terminal domain of one monomer is frequently found in contact with residues 135-164 encompassing the a, b, and c strands of the Greek Key motif 4 of the second molecule. The present results suggest that γD-crystallin may polymerize through successive domain swapping of those three C-terminal β-strands leading to age-onset cataract, as an evolutionary cost of its very high stability. Alanine substitutions of the hydrophobic residues in those aggregation-prone β-strands, such as L145 and M147, hinder domain swapping as a pathway toward dimerization. These findings thus provide critical molecular insights onto the initial stages of age-onset cataract, which is important for understanding protein aggregation diseases.
authors.affiliation: IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.
authors.forename: Payel
authors.initials: P
authors.lastname: Das
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: King
authors.forename: Ruhong
authors.initials: R
authors.lastname: Zhou
mesh_terms: D002386:Cataract / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011489:Protein Denaturation; D038222:gamma-Crystallins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D038222:gamma-Crystallins