%0 Journal Article
%T Site-Directed Mutations in the C-Terminal Extension of Human ¦ÁB-Crystallin Affect Chaperone Function and Block Amyloid Fibril Formation
%A Teresa M. Treweek
%A Heath Ecroyd
%A Danielle M. Williams
%A Sarah Meehan
%A John A. Carver
%A Mark J. Walker
%J PLOS ONE
%D 2007
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0001046
%X Background Alzheimer's, Parkinson's and Creutzfeldt-Jakob disease are associated with inappropriate protein deposition and ordered amyloid fibril assembly. Molecular chaperones, including ¦ÁB-crystallin, play a role in the prevention of protein deposition. Methodology/Principal Findings A series of site-directed mutants of the human molecular chaperone, ¦ÁB-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 ¦ÁB-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 ¦ÁB-crystallin resulted in proteins that had improved chaperone activity against amyloid fibril forming target proteins compared to the wild-type protein. Conclusions/Significance Together, our results highlight the important role of the C-terminal region of ¦ÁB-crystallin in regulating its secondary, tertiary and quaternary structure and conferring thermostability to the protein. The capacity to genetically modify ¦ÁB-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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001046