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.
Janowski
R
R
Department of Crystallography, Faculty of Chemistry, A. Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland.
Kozak
M
M
Jankowska
E
E
Grzonka
Z
Z
Grubb
A
A
Abrahamson
M
M
Jaskolski
M
M
D000595:Amino Acid Sequence; D000686:Amyloidosis; D000818:Animals; D002645:Chickens; D018360:Crystallography, X-Ray; D055316:Cystatin C; D015891:Cystatins / Q000737:chemistry* / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D007930:Leucine / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins; D007930:Leucine