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

Summary, in English

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: Robert Janowski; Maciej Kozak; Elzbieta Jankowska; Zbigniew Grzonka; Anders Grubb; Magnus Abrahamson; Mariusz Jaskolski
• Department/s: Division of Clinical Chemistry and Pharmacology; Protease Inhibitor Research
• Publishing year: 2001
• Language: English
• Pages: 316-320
• Publication/Series: Nature Structural Biology
• Volume: 8
• Issue: 4
• Full text: - 2 MB; Download statistics
• Links: http://dx.doi.org/10.1038/86188
• Document type: Journal article
• Publisher: Nature Publishing Group
• Topic: Pharmacology and Toxicology; Medicinal Chemistry
• Status: Published
• Research group: Protease Inhibitor Research
• ISBN/ISSN/Other: ISSN: 1072-8368