Article The Structure of the Cataract-Causing P23T Mutant of Human
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Jung-2009-The Structure of the Cataract-Causing.pdf
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3.62 MB
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Author(s)
Wang, Yongting
King, Jonathan Alan
Jung, Jinwon
Byeon, In-Ja L.
Gronenborn, Angela M.
Alternative Title
The Structure of the Cataract-Causing P23T Mutant of Human γD-Crystallin Exhibits Distinctive Local Conformational and Dynamic Changes
Date Issued
February 2009
Journal
Biochemistry
Publisher
American Chemical Society (ACS)
Citation
Jung, Jinwon et al. “The Structure of the Cataract-Causing P23T Mutant of Human γD-Crystallin Exhibits Distinctive Local Conformational and Dynamic Changes.” Biochemistry 48.12 (2009): 2597–2609. © 2009 American Chemical Society
Version
Final published version
Abstract
Crystallins are major proteins of the eye lens and essential for lens transparency. Mutations and aging of crystallins cause cataracts, the predominant cause of blindness in the world. In human γD-crystallin, the P23T mutant is associated with congenital cataracts. Until now, no atomic structural information has been available for this variant. Biophysical analyses of this mutant protein have revealed dramatically reduced solubility compared to that of the wild-type protein due to self-association into higher-molecular weight clusters and aggregates that retain a nativelike conformation within the monomers [Pande, A., et al. (2005) Biochemistry 44, 2491−2500]. To elucidate the structure and local conformation around the mutation site, we have determined the solution structure and characterized the protein’s dynamic behavior by NMR. Although the global structure is very similar to the X-ray structure of wild-type γD-crystallin, pivotal local conformational and dynamic differences are caused by the threonine substitution. In particular, in the P23T mutant, the imidazole ring of His22 switches from the predominant Nε2 tautomer in the wild-type protein to the Nδ1 tautomer, and an altered motional behavior of the associated region in the protein is observed. The data support structural changes that may initiate aggregation or polymerization by the mutant protein.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1021/bi802292q
