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

Journal Article


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Abstract


  • Background

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

    Methodology/Principal Findings

    A series of site-directed mutants of the human molecular chaperone, ÃÂÃÂÃÂñB-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 ÃÂÃÂÃÂñB-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 ÃÂÃÂÃÂñB-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 ÃÂÃÂÃÂñB-crystallin in regulating its secondary, tertiary and quaternary structure and conferring thermostability to the protein. The capacity to genetically modify ÃÂÃÂÃÂñB-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.

Authors


  •   Treweek, Teresa M.
  •   Ecroyd, Heath
  •   Williams, Danielle M. (external author)
  •   Meehan, Sarah (external author)
  •   Carver, John A. (external author)
  •   Walker, Mark J. (external author)

Publication Date


  • 2007

Citation


  • Treweek, T. M., Ecroyd, H. W., Williams, D. M., Meehan, S., Carver, J. A. & Walker, M. J. (2007). Site-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation. PLoS One, (10), 1-10.

Scopus Eid


  • 2-s2.0-42349107955

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1056&context=hbspapers

Ro Metadata Url


  • http://ro.uow.edu.au/hbspapers/51

Number Of Pages


  • 9

Start Page


  • 1

End Page


  • 10

Issue


  • 10

Abstract


  • Background

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

    Methodology/Principal Findings

    A series of site-directed mutants of the human molecular chaperone, ÃÂÃÂÃÂñB-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 ÃÂÃÂÃÂñB-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 ÃÂÃÂÃÂñB-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 ÃÂÃÂÃÂñB-crystallin in regulating its secondary, tertiary and quaternary structure and conferring thermostability to the protein. The capacity to genetically modify ÃÂÃÂÃÂñB-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.

Authors


  •   Treweek, Teresa M.
  •   Ecroyd, Heath
  •   Williams, Danielle M. (external author)
  •   Meehan, Sarah (external author)
  •   Carver, John A. (external author)
  •   Walker, Mark J. (external author)

Publication Date


  • 2007

Citation


  • Treweek, T. M., Ecroyd, H. W., Williams, D. M., Meehan, S., Carver, J. A. & Walker, M. J. (2007). Site-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation. PLoS One, (10), 1-10.

Scopus Eid


  • 2-s2.0-42349107955

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1056&context=hbspapers

Ro Metadata Url


  • http://ro.uow.edu.au/hbspapers/51

Number Of Pages


  • 9

Start Page


  • 1

End Page


  • 10

Issue


  • 10