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The Structure of the Cataract-Causing P23T Mutant of Human γD-Crystallin Exhibits Distinctive Local Conformational and Dynamic Changes†,‡

[Image: see text] 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 at...

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Autores principales: Jung, Jinwon, Byeon, In-Ja L., Wang, Yongting, King, Jonathan, Gronenborn, Angela M.
Formato: Texto
Lenguaje:English
Publicado: American Chemical Society 2009
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722838/
https://www.ncbi.nlm.nih.gov/pubmed/19216553
http://dx.doi.org/10.1021/bi802292q
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author Jung, Jinwon
Byeon, In-Ja L.
Wang, Yongting
King, Jonathan
Gronenborn, Angela M.
author_facet Jung, Jinwon
Byeon, In-Ja L.
Wang, Yongting
King, Jonathan
Gronenborn, Angela M.
author_sort Jung, Jinwon
collection PubMed
description [Image: see text] 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.
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spelling pubmed-27228382009-08-10 The Structure of the Cataract-Causing P23T Mutant of Human γD-Crystallin Exhibits Distinctive Local Conformational and Dynamic Changes†,‡ Jung, Jinwon Byeon, In-Ja L. Wang, Yongting King, Jonathan Gronenborn, Angela M. Biochemistry [Image: see text] 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. American Chemical Society 2009-02-13 2009-03-31 /pmc/articles/PMC2722838/ /pubmed/19216553 http://dx.doi.org/10.1021/bi802292q Text en Copyright © 2009 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org.
spellingShingle Jung, Jinwon
Byeon, In-Ja L.
Wang, Yongting
King, Jonathan
Gronenborn, Angela M.
The Structure of the Cataract-Causing P23T Mutant of Human γD-Crystallin Exhibits Distinctive Local Conformational and Dynamic Changes†,‡
title The Structure of the Cataract-Causing P23T Mutant of Human γD-Crystallin Exhibits Distinctive Local Conformational and Dynamic Changes†,‡
title_full The Structure of the Cataract-Causing P23T Mutant of Human γD-Crystallin Exhibits Distinctive Local Conformational and Dynamic Changes†,‡
title_fullStr The Structure of the Cataract-Causing P23T Mutant of Human γD-Crystallin Exhibits Distinctive Local Conformational and Dynamic Changes†,‡
title_full_unstemmed The Structure of the Cataract-Causing P23T Mutant of Human γD-Crystallin Exhibits Distinctive Local Conformational and Dynamic Changes†,‡
title_short The Structure of the Cataract-Causing P23T Mutant of Human γD-Crystallin Exhibits Distinctive Local Conformational and Dynamic Changes†,‡
title_sort structure of the cataract-causing p23t mutant of human γd-crystallin exhibits distinctive local conformational and dynamic changes†,‡
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722838/
https://www.ncbi.nlm.nih.gov/pubmed/19216553
http://dx.doi.org/10.1021/bi802292q
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