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

The crystal structure of human cystatin C, a protein with amyloidogenic pro perties and a potent inhibitor of cysteine proteases, reveals how the prote in refolds to produce very tight two-fold symmetric dimers while retaining the secondary structure of the monomeric form. The dimerization occurs thro ugh three-dimensional domain swapping, a mechanism for forming oligomeric p roteins. The reconstituted monomer-like domains are similar to chicken cyst atin except for one inhibitory loop that unfolds to form the 'open interfac e' of the dimer. The structure explains the tendency of human cystatin C to dimerize and suggests a mechanism for its aggregation in the brain arterie s of elderly people with amyloid angiopathy, A more severe 'conformational disease' is associated with the L68Q mutant of human cystatin C, which caus es 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 interm ediate less unstable. Higher aggregates may arise through the three-dimensi onal domain-swapping mechanism occurring in an open-ended fashion in which partially unfolded molecules are linked into infinite chains.