8H0R

Crystal structure of a cataract-causing crystallin mutant (mouse CRYBB1 Y202X)

Summary for 8H0R

• Entry DOI: 10.2210/pdb8h0r/pdb
• Descriptor: Beta-crystallin B1B (2 entities in total)
• Functional Keywords: crystallin crybb1, trancated mutant, structural protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 21518.23

Authors

Jing, X.,Gong, P. (deposition date: 2022-09-30, release date: 2023-07-05, Last modification date: 2023-08-16)

Primary citation

Jing, X.,Zhu, M.,Lu, X.,Wei, P.,Shi, L.,Zhang, B.Y.,Xu, Y.,Tang, Y.P.,Xiang, D.M.,Gong, P.
Cataract-causing Y204X mutation of crystallin protein CRY beta B1 promotes its C-terminal degradation and higher-order oligomerization.
J.Biol.Chem., 299:104953-104953, 2023

PubMed Abstract: Crystallin proteins are a class of main structural proteins of the vertebrate eye lens, and their solubility and stability directly determine transparency and refractive power of the lens. Mutation in genes that encode these crystallin proteins is the most common cause for congenital cataracts. Despite extensive studies, the pathogenic and molecular mechanisms that effect congenital cataracts remain unclear. In this study, we identified a novel mutation in CRYBB1 from a congenital cataract family, and demonstrated that this mutation led to an early termination of mRNA translation, resulting in a 49-residue C-terminally truncated CRYβB1 protein. We show this mutant is susceptible to proteolysis, which allowed us to determine a 1.2-Å resolution crystal structure of CRYβB1 without the entire C-terminal domain. In this crystal lattice, we observed that two N-terminal domain monomers form a dimer that structurally resembles the WT monomer, but with different surface characteristics. Biochemical analyses and cell-based data also suggested that this mutant is significantly more liable to aggregate and degrade compared to WT CRYβB1. Taken together, our results provide an insight into the mechanism regarding how a mutant crystalin contributes to the development of congenital cataract possibly through alteration of inter-protein interactions that result in protein aggregation.

PubMed: 37356717
DOI: 10.1016/j.jbc.2023.104953

Experimental method

X-RAY DIFFRACTION (1.201 Å)