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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/168514
- author
- Wahlbom, Maria
LU
; Wang, Xin
LU
; Lindström, Veronica
LU
; Carlemalm, Eric
LU
; Jaskolski, Mariusz
and Grubb, Anders
LU
- organization
- publishing date
- 2007
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 282
- issue
- 25
- pages
- 18318 - 18326
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000247302000038
- scopus:34547111066
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M611368200
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Electron Microscopy Unit (013100002), Division of Clinical Chemistry and Pharmacology (013250300)
- 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
- 2016-04-01 12:15:22
- date last changed
- 2023-03-01 18:55:35
@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 = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{Fibrillogenic oligomers of human cystatin C are formed by propagated domain swapping.}},
url = {{https://lup.lub.lu.se/search/files/2847716/625964.pdf}},
doi = {{10.1074/jbc.M611368200}},
volume = {{282}},
year = {{2007}},
}