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Fibrillogenic oligomers of human cystatin C are formed by propagated domain swapping.

Wahlbom, Maria LU ; Wang, Xin LU ; Lindström, Veronica LU ; Carlemalm, Eric LU ; Jaskolski, Mariusz and Grubb, Anders LU (2007) In Journal of Biological Chemistry 282(25). p.18318-18326
Abstract
Cystatin C and the prion protein have been shown to form dimers via three-dimensional domain swapping, and this process has also been hypothesized to be involved in amyloidogenesis. Production of oligomers of other amyloidogenic proteins has been reported to precede fibril formation, suggesting oligomers as intermediates in fibrillogenesis. A variant of cystatin C, with a Leu(68)-> Gln substitution, is highly amyloidogenic, and carriers of this mutation suffer from massive cerebral amyloidosis leading to brain hemorrhage and death in early adulthood. This work describes doughnut-shaped oligomers formed by wild type and L68Q cystatin C upon incubation of the monomeric proteins. Purified oligomers of cystatin C are shown to fibrillize... (More)
Cystatin C and the prion protein have been shown to form dimers via three-dimensional domain swapping, and this process has also been hypothesized to be involved in amyloidogenesis. Production of oligomers of other amyloidogenic proteins has been reported to precede fibril formation, suggesting oligomers as intermediates in fibrillogenesis. A variant of cystatin C, with a Leu(68)-> Gln substitution, is highly amyloidogenic, and carriers of this mutation suffer from massive cerebral amyloidosis leading to brain hemorrhage and death in early adulthood. This work describes doughnut-shaped oligomers formed by wild type and L68Q cystatin C upon incubation of the monomeric proteins. Purified oligomers of cystatin C are shown to fibrillize faster and at a lower concentration than the monomeric protein, indicating a role of the oligomers as fibril-assembly intermediates. Moreover, the present work demonstrates that three-dimensional domain swapping is involved in the formation of the oligomers, because variants of monomeric cystatin C, stabilized against three-dimensional domain swapping by engineered disulfide bonds, do not produce oligomers upon incubation under non-reducing conditions. Redox experiments using wild type and stabilized cystatin C strongly suggest that the oligomers, and thus probably the fibrils as well, are formed by propagated domain swapping rather than by assembly of domain-swapped cystatin C dimers. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
282
issue
25
pages
18318 - 18326
publisher
ASBMB
external identifiers
  • wos:000247302000038
  • scopus:34547111066
ISSN
1083-351X
DOI
10.1074/jbc.M611368200
language
English
LU publication?
yes
id
2fbfb770-a5bf-45a6-ba6a-aad23f4a115d (old id 168514)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17470433&dopt=Abstract
date added to LUP
2007-07-06 10:05:55
date last changed
2017-07-30 03:46:20
@article{2fbfb770-a5bf-45a6-ba6a-aad23f4a115d,
  abstract     = {Cystatin C and the prion protein have been shown to form dimers via three-dimensional domain swapping, and this process has also been hypothesized to be involved in amyloidogenesis. Production of oligomers of other amyloidogenic proteins has been reported to precede fibril formation, suggesting oligomers as intermediates in fibrillogenesis. A variant of cystatin C, with a Leu(68)-> Gln substitution, is highly amyloidogenic, and carriers of this mutation suffer from massive cerebral amyloidosis leading to brain hemorrhage and death in early adulthood. This work describes doughnut-shaped oligomers formed by wild type and L68Q cystatin C upon incubation of the monomeric proteins. Purified oligomers of cystatin C are shown to fibrillize faster and at a lower concentration than the monomeric protein, indicating a role of the oligomers as fibril-assembly intermediates. Moreover, the present work demonstrates that three-dimensional domain swapping is involved in the formation of the oligomers, because variants of monomeric cystatin C, stabilized against three-dimensional domain swapping by engineered disulfide bonds, do not produce oligomers upon incubation under non-reducing conditions. Redox experiments using wild type and stabilized cystatin C strongly suggest that the oligomers, and thus probably the fibrils as well, are formed by propagated domain swapping rather than by assembly of domain-swapped cystatin C dimers.},
  author       = {Wahlbom, Maria and Wang, Xin and Lindström, Veronica and Carlemalm, Eric and Jaskolski, Mariusz and Grubb, Anders},
  issn         = {1083-351X},
  language     = {eng},
  number       = {25},
  pages        = {18318--18326},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Fibrillogenic oligomers of human cystatin C are formed by propagated domain swapping.},
  url          = {http://dx.doi.org/10.1074/jbc.M611368200},
  volume       = {282},
  year         = {2007},
}