Site-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation.

<h4>Background</h4>Alzheimer's, Parkinson's and Creutzfeldt-Jakob disease are associated with inappropriate protein deposition and ordered amyloid fibril assembly. Molecular chaperones, including alphaB-crystallin, play a role in the prevention of protein deposition.<h4>M...

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Autores principales:	Teresa M Treweek, Heath Ecroyd, Danielle M Williams, Sarah Meehan, John A Carver, Mark J Walker
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2007
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d49f0f914aee4690b4b52bada14e2151
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spelling	oai:doaj.org-article:d49f0f914aee4690b4b52bada14e21512021-11-25T06:10:41ZSite-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation.1932-620310.1371/journal.pone.0001046https://doaj.org/article/d49f0f914aee4690b4b52bada14e21512007-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0001046https://doaj.org/toc/1932-6203<h4>Background</h4>Alzheimer's, Parkinson's and Creutzfeldt-Jakob disease are associated with inappropriate protein deposition and ordered amyloid fibril assembly. Molecular chaperones, including alphaB-crystallin, play a role in the prevention of protein deposition.<h4>Methodology/principal findings</h4>A series of site-directed mutants of the human molecular chaperone, alphaB-crystallin, were constructed which focused on the flexible C-terminal extension of the protein. We investigated the structural role of this region as well as its role in the chaperone function of alphaB-crystallin under different types of protein aggregation, i.e. disordered amorphous aggregation and ordered amyloid fibril assembly. It was found that mutation of lysine and glutamic acid residues in the C-terminal extension of alphaB-crystallin resulted in proteins that had improved chaperone activity against amyloid fibril forming target proteins compared to the wild-type protein.<h4>Conclusions/significance</h4>Together, our results highlight the important role of the C-terminal region of alphaB-crystallin in regulating its secondary, tertiary and quaternary structure and conferring thermostability to the protein. The capacity to genetically modify alphaB-crystallin for improved ability to block amyloid fibril formation provides a platform for the future use of such engineered molecules in treatment of diseases caused by amyloid fibril formation.Teresa M TreweekHeath EcroydDanielle M WilliamsSarah MeehanJohn A CarverMark J WalkerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 2, Iss 10, p e1046 (2007)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Teresa M Treweek Heath Ecroyd Danielle M Williams Sarah Meehan John A Carver Mark J Walker Site-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation.
description	<h4>Background</h4>Alzheimer's, Parkinson's and Creutzfeldt-Jakob disease are associated with inappropriate protein deposition and ordered amyloid fibril assembly. Molecular chaperones, including alphaB-crystallin, play a role in the prevention of protein deposition.<h4>Methodology/principal findings</h4>A series of site-directed mutants of the human molecular chaperone, alphaB-crystallin, were constructed which focused on the flexible C-terminal extension of the protein. We investigated the structural role of this region as well as its role in the chaperone function of alphaB-crystallin under different types of protein aggregation, i.e. disordered amorphous aggregation and ordered amyloid fibril assembly. It was found that mutation of lysine and glutamic acid residues in the C-terminal extension of alphaB-crystallin resulted in proteins that had improved chaperone activity against amyloid fibril forming target proteins compared to the wild-type protein.<h4>Conclusions/significance</h4>Together, our results highlight the important role of the C-terminal region of alphaB-crystallin in regulating its secondary, tertiary and quaternary structure and conferring thermostability to the protein. The capacity to genetically modify alphaB-crystallin for improved ability to block amyloid fibril formation provides a platform for the future use of such engineered molecules in treatment of diseases caused by amyloid fibril formation.
format	article
author	Teresa M Treweek Heath Ecroyd Danielle M Williams Sarah Meehan John A Carver Mark J Walker
author_facet	Teresa M Treweek Heath Ecroyd Danielle M Williams Sarah Meehan John A Carver Mark J Walker
author_sort	Teresa M Treweek
title	Site-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation.
title_short	Site-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation.
title_full	Site-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation.
title_fullStr	Site-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation.
title_full_unstemmed	Site-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation.
title_sort	site-directed mutations in the c-terminal extension of human alphab-crystallin affect chaperone function and block amyloid fibril formation.
publisher	Public Library of Science (PLoS)
publishDate	2007
url	https://doaj.org/article/d49f0f914aee4690b4b52bada14e2151
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Site-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation.

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