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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?

Rodziewicz-Motowidlo, S ; Wahlbom, Maria LU ; Wang, Xin LU ; Lagiewka, J ; Janowski, R ; Jaskolski, M ; Grubb, Anders LU and Grzonka, Z (2006) In Journal of Structural Biology 154(1). p.68-78
Abstract
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... (More)
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. (Less)
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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
single-point mutation, amyloidosis, conformational change, human cystatin C, molecular dynamics simulation
in
Journal of Structural Biology
volume
154
issue
1
pages
68 - 78
publisher
Elsevier
external identifiers
  • pmid:16446102
  • wos:000236561000006
  • scopus:33645003090
ISSN
1095-8657
DOI
10.1016/j.jsb.2005.11.015
language
English
LU publication?
yes
id
f471bad6-c110-4629-8782-9cfce2242748 (old id 414383)
date added to LUP
2016-04-01 16:25:33
date last changed
2021-02-17 03:52:43
@article{f471bad6-c110-4629-8782-9cfce2242748,
  abstract     = {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.},
  author       = {Rodziewicz-Motowidlo, S and Wahlbom, Maria and Wang, Xin and Lagiewka, J and Janowski, R and Jaskolski, M and Grubb, Anders and Grzonka, Z},
  issn         = {1095-8657},
  language     = {eng},
  number       = {1},
  pages        = {68--78},
  publisher    = {Elsevier},
  series       = {Journal of Structural Biology},
  title        = {Checking the conformational stability of cystatin C and its L68Q variant by molecular dynamics studies: Why is the L68Q variant amyloidogenic?},
  url          = {http://dx.doi.org/10.1016/j.jsb.2005.11.015},
  doi          = {10.1016/j.jsb.2005.11.015},
  volume       = {154},
  year         = {2006},
}