1G96

HUMAN CYSTATIN C; DIMERIC FORM WITH 3D DOMAIN SWAPPING

Summary for 1G96

• Entry DOI: 10.2210/pdb1g96/pdb
• Related: 1a67 1cew 1dvc 1stf
• Descriptor: CYSTATIN C, CHLORIDE ION, GLYCEROL, ... (4 entities in total)
• Functional Keywords: human cystatin c dimer, 3d domain swapping, amyloid formation, inhibitor of c1 and c13 cysteine proteases, amyloid angiopathy and cerebral hemorrhage, hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P01034
• Total number of polymer chains: 1
• Total formula weight: 13492.69

Authors

Janowski, R.,Kozak, M.,Jankowska, E.,Grzonka, Z.,Grubb, A.,Abrahamson, M.,Jaskolski, M. (deposition date: 2000-11-22, release date: 2001-04-06, Last modification date: 2024-11-20)

Primary citation

Janowski, R.,Kozak, M.,Jankowska, E.,Grzonka, Z.,Grubb, A.,Abrahamson, M.,Jaskolski, M.
Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping.
Nat.Struct.Biol., 8:316-320, 2001

PubMed Abstract: 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.

PubMed: 11276250
DOI: 10.1038/86188

Experimental method

X-RAY DIFFRACTION (2.5 Å)