| Autor: |
Janowski, Robert, Kozak, Maciej, Jankowska, Elzbieta, Grzonka, Zbigniew, Grubb, Anders, Abrahamson, Magnus, Jaskolski, Mariusz |
| Jazyk: |
angličtina |
| Rok vydání: |
2001 |
| Předmět: |
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| Zdroj: |
Nature Structural Biology; 8(4), pp 316-320 (2001) |
| ISSN: |
1072-8368 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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