1g96

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.

Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping., Janowski R, Kozak M, Jankowska E, Grzonka Z, Grubb A, Abrahamson M, Jaskolski M, Nat Struct Biol. 2001 Apr;8(4):316-20. PMID:11276250

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Categories: Homo sapiens | Abrahamson, M. | Grubb, A. | Grzonka, Z. | Jankowska, E. | Janowski, R. | Jaskolski, M. | Kozak, M. | 3d domain swapping | Amyloid angiopathy and cerebral hemorrhage | Amyloid formation | Human cystatin c dimer | Hydrolase inhibitor | Inhibitor of c1 and c13 cysteine protease