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


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.

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Figure 1: Primary, secondary, tertiary and quaternary structure of HCC.
Figure 2: Schematic illustrations of how HCC oligomers are formed.
Figure 3: Electron density maps.

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The research of M.J. was supported by an International Research Scholar's award from the Howard Hughes Medical Institute. This research was sponsored by grants from the State Committee for Scientific Research, from the Swedish Medical Research Council, and from the A. Osterlund, A. Pahlsson and J. Kock Foundations. We thank V. Lindström, A.-C. Löfström, B. Gerhartz, and M. Alvarez-Fernandez for assistance with protein expression and purification, G. Bujacz for help with data collection, and Z. Otwinowski for advice on data processing.

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Correspondence to Mariusz Jaskolski.

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Janowski, R., Kozak, M., Jankowska, E. et al. Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping. Nat Struct Mol Biol 8, 316–320 (2001).

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