Cataract-linked mutation R188H promotes βB2-crystallin aggregation and fibrillization during acid denaturation.
Cataract is characterized by the formation of light-scattering protein aggregates in the lens. β/γ-Crystallins are the predominant structural proteins in the cytosol of lens fiber cells, and more than fifty β/γ-crystallin mutations have been linked to autosomal dominant congenital cataract. However, the structural role of these mutations in the formation of the core structures of amorphous aggregates or amyloid-like fibrils has not been elucidated yet. In this research, we studied the effects of the V187M and R188H mutations on the aggregation and fibrillization of βB2-crystallin during acid denaturation. The behavior of V187M was the same as the WT protein, suggesting that the residue at position 187 contributed little to the aggregation/fibrillization process. R188H promoted the formation of amorphous aggregates at pH above 3 and accelerated fibrillization at pH 3. The distinct behaviors of the mutants suggested that the residue at position 188 might play a regulatory role in βB2-crystallin aggregation/fibrillization but not reside in the core of the aggregates/fibrils.
MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, China; State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Yi-Bo
YB
Xi
Eye Center of the 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou 310009, China.
Kai
K
Zhang
State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
An-Bang
AB
Dai
MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Shang-Rong
SR
Ji
Eye Center of the 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou 310009, China.
Ke
K
Yao
State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: ybyan@tsinghua.edu.cn.
Yong-Bin
YB
Yan
D000143:Acids / Q000737:chemistry; D001120:Arginine / Q000737:chemistry / Q000235:genetics; D002386:Cataract / Q000235:genetics* / Q000378:metabolism*; D006639:Histidine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009154:Mutation; D011489:Protein Denaturation; D038206:beta-Crystallin B Chain / Q000737:chemistry* / Q000235:genetics*
D000143:Acids; D038206:beta-Crystallin B Chain; C113634:beta-crystallin B2; D006639:Histidine; D001120:Arginine
Acid denaturation; Autosomal dominant congenital nuclear cataract; Inherited mutation; Protein aggregation; Protein fibrillization; βB2-crystallin