Article The Structure of the Cataract-Causing P23T Mutant of Human
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 in...
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| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2012
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| Online Access: | http://hdl.handle.net/1721.1/73200 https://orcid.org/0000-0001-6174-217X |
| _version_ | 1811098082862956544 |
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| author | Wang, Yongting King, Jonathan Alan Jung, Jinwon Byeon, In-Ja L. Gronenborn, Angela M. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Wang, Yongting King, Jonathan Alan Jung, Jinwon Byeon, In-Ja L. Gronenborn, Angela M. |
| author_sort | Wang, Yongting |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T17:09:38Z |
| format | Article |
| id | mit-1721.1/73200 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:09:38Z |
| publishDate | 2012 |
| publisher | American Chemical Society (ACS) |
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| spelling | mit-1721.1/732002022-09-30T00:05:28Z Article The Structure of the Cataract-Causing P23T Mutant of Human The Structure of the Cataract-Causing P23T Mutant of Human γD-Crystallin Exhibits Distinctive Local Conformational and Dynamic Changes Wang, Yongting King, Jonathan Alan Jung, Jinwon Byeon, In-Ja L. Gronenborn, Angela M. Massachusetts Institute of Technology. Department of Biology Wang, Yongting King, Jonathan Alan 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. National Institutes of Health (U.S.) (Grant GM 17980) National Eye Institute (Grant EY 015834) 2012-09-27T13:07:51Z 2012-09-27T13:07:51Z 2009-02 2009-02 Article http://purl.org/eprint/type/JournalArticle 0006-2960 1520-4995 http://hdl.handle.net/1721.1/73200 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 https://orcid.org/0000-0001-6174-217X en_US http://dx.doi.org/10.1021/bi802292q Biochemistry Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) ACS |
| spellingShingle | Wang, Yongting King, Jonathan Alan Jung, Jinwon Byeon, In-Ja L. Gronenborn, Angela M. Article The Structure of the Cataract-Causing P23T Mutant of Human |
| title | Article The Structure of the Cataract-Causing P23T Mutant of Human |
| title_full | Article The Structure of the Cataract-Causing P23T Mutant of Human |
| title_fullStr | Article The Structure of the Cataract-Causing P23T Mutant of Human |
| title_full_unstemmed | Article The Structure of the Cataract-Causing P23T Mutant of Human |
| title_short | Article The Structure of the Cataract-Causing P23T Mutant of Human |
| title_sort | article the structure of the cataract causing p23t mutant of human |
| url | http://hdl.handle.net/1721.1/73200 https://orcid.org/0000-0001-6174-217X |
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