Crystal structure of human cystatin C stabilized against amyloid formation
Por:
Kolodziejczyk R., Michalska K., Hernandez-Santoyo A., Wahlbom M., Grubb A., Jaskolski M.
Publicada:
1 abr 2010
Resumen:
Human cystatin C (HCC) is a family 2 cystatin inhibitor of papain-like (C1) and legumain-related (C13) cysteine proteases. In pathophysiological processes, the nature of which is not understood, HCC is codeposited in the amyloid plaques of Alzheimer's disease or Down's syndrome. The amyloidogenic properties of HCC are greatly increased in a naturally occurring L68Q variant, resulting in fatal cerebral amyloid angiopathy in early adult life. In all crystal structures of cystatin C studied to date, the protein has been found to form 3D domain-swapped dimers, created through a conformational change of a beta-hairpin loop, L1, from the papain-binding epitope. We have created monomer-stabilized human cystatin C, with an engineered disulfide bond (L47C)-(G69C) between the structural elements that become separated upon domain swapping. The mutant has drastically reduced dimerization and fibril formation properties, but its inhibition of papain is unaltered. The structure confirms the success
Filiaciones:
Kolodziejczyk R.:
Faculty of Chemistry, Department of Crystallography, A. Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
Michalska K.:
Faculty of Chemistry, Department of Crystallography, A. Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
Hernandez-Santoyo A.:
Univ Nacl Autonoma Mexico, Inst Quim, Mexico City 04510, DF, Mexico
Wahlbom M.:
Department of Clinical Chemistry, Lund University, Sweden
Grubb A.:
Department of Clinical Chemistry, Lund University, Sweden
Jaskolski M.:
Faculty of Chemistry, Department of Crystallography, A. Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
Center for Biocrystallographic Research, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
Bronze
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