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Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping
R Janowski1, M Kozak, E Jankowska
1Department of Crystallography, Faculty of Chemistry, A. Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland.
Nature Structural Biology
|March 29, 2001
Summary
Human cystatin C refolds into dimers via domain swapping, explaining its aggregation in amyloid angiopathy. A mutation (L68Q) destabilizes monomers, leading to severe amyloidosis and disease.
Area of Science:
- Structural biology
- Biochemistry
- Protein aggregation
Background:
- Human cystatin C is a cysteine protease inhibitor with amyloidogenic properties.
- Amyloid angiopathy and conformational diseases are linked to cystatin C aggregation.
Purpose of the Study:
- To elucidate the crystal structure of human cystatin C dimers.
- To understand the mechanism of dimerization and its relation to amyloid formation.
- To investigate the structural basis of the L68Q mutation's severe phenotype.
Main Methods:
- X-ray crystallography to determine the structure of cystatin C dimers.
- Structural analysis to compare monomeric and dimeric forms.
- Analysis of the L68Q mutant structure.
Main Results:
- Human cystatin C forms tight, two-fold symmetric dimers through three-dimensional domain swapping.
- Dimerization retains monomer secondary structure, with one inhibitory loop forming the dimer interface.
- The L68Q mutation destabilizes monomers, facilitating aggregation and potentially infinite chain formation.
Conclusions:
- The crystal structure explains cystatin C's dimerization and aggregation propensity in amyloid angiopathy.
- The L68Q mutation exacerbates aggregation by destabilizing monomers.
- Three-dimensional domain swapping is a key mechanism for cystatin C oligomerization and pathogenesis.