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Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping

Janowski, Robert; Kozak, Maciej; Jankowska, Elzbieta; Grzonka, Zbigniew; Grubb, Anders LU ; Abrahamson, Magnus LU and Jaskolski, Mariusz (2001) In Nature Structural Biology 8(4). p.316-320
Abstract
The crystal structure of human cystatin C, a protein with amyloidogenic properties and a potent inhibitor of cysteine proteases, reveals how the protein refolds to produce very tight two-fold symmetric dimers while retaining the secondary structure of the monomeric form. The dimerization occurs through three-dimensional domain swapping, a mechanism for forming oligomeric proteins. The reconstituted monomer-like domains are similar to chicken cystatin except for one inhibitory loop that unfolds to form the open interface of the dimer. The structure explains the tendency of human cystatin C to dimerize and suggests a mechanism for its aggregation in the brain arteries of elderly people with amyloid angiopathy. A more severe conformational... (More)
The crystal structure of human cystatin C, a protein with amyloidogenic properties and a potent inhibitor of cysteine proteases, reveals how the protein refolds to produce very tight two-fold symmetric dimers while retaining the secondary structure of the monomeric form. The dimerization occurs through three-dimensional domain swapping, a mechanism for forming oligomeric proteins. The reconstituted monomer-like domains are similar to chicken cystatin except for one inhibitory loop that unfolds to form the open interface of the dimer. The structure explains the tendency of human cystatin C to dimerize and suggests a mechanism for its aggregation in the brain arteries of elderly people with amyloid angiopathy. A more severe conformational disease is associated with the L68Q mutant of human cystatin C, which causes massive amyloidosis, cerebral hemorrhage and death in young adults. The structure of the three-dimensional domain-swapped dimers shows how the L68Q mutation destabilizes the monomers and makes the partially unfolded intermediate less unstable. Higher aggregates may arise through the three-dimensional domain-swapping mechanism occurring in an open-ended fashion in which partially unfolded molecules are linked into infinite chains. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Structural Biology
volume
8
issue
4
pages
316 - 320
publisher
Nature Publishing Group
external identifiers
  • wos:000167811300013
  • scopus:0035069135
ISSN
1072-8368
DOI
10.1038/86188
language
English
LU publication?
yes
id
ed769437-600d-4346-9701-32de2da7257a (old id 131360)
date added to LUP
2007-07-05 10:55:41
date last changed
2018-05-29 10:41:20
@article{ed769437-600d-4346-9701-32de2da7257a,
  abstract     = {The crystal structure of human cystatin C, a protein with amyloidogenic properties and a potent inhibitor of cysteine proteases, reveals how the protein refolds to produce very tight two-fold symmetric dimers while retaining the secondary structure of the monomeric form. The dimerization occurs through three-dimensional domain swapping, a mechanism for forming oligomeric proteins. The reconstituted monomer-like domains are similar to chicken cystatin except for one inhibitory loop that unfolds to form the open interface of the dimer. The structure explains the tendency of human cystatin C to dimerize and suggests a mechanism for its aggregation in the brain arteries of elderly people with amyloid angiopathy. A more severe conformational disease is associated with the L68Q mutant of human cystatin C, which causes massive amyloidosis, cerebral hemorrhage and death in young adults. The structure of the three-dimensional domain-swapped dimers shows how the L68Q mutation destabilizes the monomers and makes the partially unfolded intermediate less unstable. Higher aggregates may arise through the three-dimensional domain-swapping mechanism occurring in an open-ended fashion in which partially unfolded molecules are linked into infinite chains.},
  author       = {Janowski, Robert and Kozak, Maciej and Jankowska, Elzbieta and Grzonka, Zbigniew and Grubb, Anders and Abrahamson, Magnus and Jaskolski, Mariusz},
  issn         = {1072-8368},
  language     = {eng},
  number       = {4},
  pages        = {316--320},
  publisher    = {Nature Publishing Group},
  series       = {Nature Structural Biology},
  title        = {Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping},
  url          = {http://dx.doi.org/10.1038/86188},
  volume       = {8},
  year         = {2001},
}