title: Cataract-linked γD-crystallin mutants have weak affinity to lens chaperones α-crystallins.
abstract: To test the hypothesis that α-crystallin chaperone activity plays a central role in maintenance of lens transparency, we investigated its interactions with γ-crystallin mutants that cause congenital cataract in mouse models. Although the two substitutions, I4F and V76D, stabilize a partially unfolded γD-crystallin intermediate, their affinities to α-crystallin are marginal even at relatively high concentrations. Detectable binding required further reduction of γD-crystallin stability which was achieved by combining the two mutations. Our results demonstrate that mutants and possibly age-damaged γ-crystallin can escape quality control by lens chaperones rationalizing the observation that they nucleate protein aggregation and lead to cataract.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mishra
authors.forename: Richard A
authors.initials: RA
authors.lastname: Stein
authors.forename: Hassane S
authors.initials: HS
authors.lastname: McHaourab
mesh_terms: D000818:Animals; D002386:Cataract / Q000151:congenital / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007908:Lens, Crystalline / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics; D056811:Unfolded Protein Response; D038201:alpha-Crystallins / Q000378:metabolism*; D038222:gamma-Crystallins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: C504903:CRYGD protein, human; D050505:Mutant Proteins; D011994:Recombinant Proteins; D038201:alpha-Crystallins; D038222:gamma-Crystallins