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Cystatin C, a major extracellular cysteine proteinase inhibitor, is deposited as amyloid in brain haemorrhage patients with hereditary cystatin C amyloid angiopathy (HCCAA). A diseasecausing mutation on the genetic level results in the substitution Leu68-&gt; Gln (L68Q) in cystatin C, which causes protein instability. Besides carrying the L68Q substitution, cystatin C in amyloid deposits isolated from patients is Nterminally truncated by 10 amino acids. To elucidate the role of the Nterminal truncation for protein stability and aggregation properties, (δ1-10,L68Q)cystatin C was produced in an Escherichia coli expression system and characterised. Unlike wildtype cystatin C, this variant rapidly dimerised under physiological conditions. Two unfolding intermediates of (δ1- 10,L68Q)cystatin C were identified, under the same pH and ionic strength conditions as required to form intermediates of fulllength L68Q cystatin C. No evidence was found that the Nterminal truncation per se alters protein stability and leads to higher forms of aggregation. Monomeric as well as dimeric L68Q cystatin C incubated with neutrophil elastase was truncated as in HCCAA patients amyloid. A protein variant with a thrombin cleavage site placed in front of residue Gly11 in L68Q cystatin C was constructed and used to confirm that the Nterminal segment is similarly accessible to proteinases in the monomeric and dimeric states of L68Q cystatin C. Thus, the Nterminal segment of L68Q cystatin C is exposed to proteolytic attack and does not seem to be involved in intramolecular contacts leading to dimerisation or higherorder aggregation. We conclude that the Nterminal truncation likely is an event secondary to amyloid formation, and of no relevance for the development of HCCAA.

Physico-Chemical Properties of the N-Terminally Truncated L68Q Cystatin C Found in Amyloid Deposits of Brain Haemorrhage Patients