Disulfide cross-links in the interaction of a cataract-linked alphaA-crystallin mutant with betaB1-crystallin.
A number of alphaA-crystallin mutants are associated with hereditary cataract including cysteine substitution at arginine 49. We report the formation of affinity-driven disulfide bonds in the interaction of alphaA-R49C with betaB1-crystallin. To mimic cysteine thiolation in the lens, betaB1-crystallin was modified by a bimane probe through a disulfide linkage. Our data suggest a mechanism whereby a transient disulfide bond occurs between alphaA- and betaB1-crystallin followed by a disulfide exchange with cysteine 49 of a neighboring alphaA-crystallin subunit. This is the first investigation of disulfide bonds in the confine of the chaperone/substrate complex where reaction rates are favored by orders of magnitude. Covalent protein cross-links are a hallmark of age-related cataract and may be a factor in its inherited form.
Kumar
M Satish
MS
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
Koteiche
Hanane A
HA
Claxton
Derek P
DP
Mchaourab
Hassane S
HS
D019943:Amino Acid Substitution; D002386:Cataract / Q000235:genetics / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009154:Mutation; D038202:alpha-Crystallin A Chain / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D038206:beta-Crystallin B Chain / Q000737:chemistry / Q000378:metabolism*
D003432:Cross-Linking Reagents; D004220:Disulfides; D038202:alpha-Crystallin A Chain; D038206:beta-Crystallin B Chain; D003545:Cysteine