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Checking the conformational stability of cystatin C and its L68Q variant by molecular dynamics studies: Why is the L68Q variant amyloidogenic?

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Author

  • S Rodziewicz-Motowidlo
  • Maria Wahlbom
  • Xin Wang
  • J Lagiewka
  • R Janowski
  • M Jaskolski
  • Anders Grubb
  • Z Grzonka

Summary, in English

Human L68Q cystatin C is one of the known human amyloidogenic proteins. In its native state it is a monomer with alpha/beta structure. Experimental evidence suggests that L68Q variant associates into dimeric intermediates and that the dimers subsequently self-assemble to form amyloid deposits and insoluble fibrils. Details of the pathway of L68Q mutant amyloid formation are unclear; however, different experimental approaches with resolutions at molecular level have provided Some clues. Probably, the stability and flexibility of monomeric L68Q variant play essential roles in the early steps of amyloid formation; thus, it is necessary to characterize early conformational changes of L68Q cystatin C monomers. In this paper, we demonstrate the possibility that the differences between the monomeric forms of wild-type (wt) cystatin C and its L68Q variant are responsible for higher tendency of the L68Q cystatin C amyloidogenesis. We started our studies with the simulations of wt and L68Q cystatin C monomers. Nanosecond time scale molecular dynamics simulations at 308 K were performed using AMBER7.0 program, The results show that the structure of the L68Q monomer was changed, relative to the wt cystatin C structure. The results support earlier speculation that the L68Q point mutation would easily lead to dimer formation. (c) 2006 Published by Elsevier Inc.

Publishing year

2006

Language

English

Pages

68-78

Publication/Series

Journal of Structural Biology

Volume

154

Issue

1

Document type

Journal article

Publisher

Elsevier

Topic

  • Medicinal Chemistry
  • Pharmacology and Toxicology

Keywords

  • single-point mutation
  • amyloidosis
  • conformational change
  • human cystatin C
  • molecular dynamics simulation

Status

Published

ISBN/ISSN/Other

  • ISSN: 1095-8657