The pentapeptide LQVVR plays a pivotal role in human cystatin C fibrillization

•An ‘aggregation-prone’ peptide, LQVVR, was predicted in human cystatin C (HCC).•The LQVVR peptide was synthesized and studied experimentally.•LQVVR self-assembles forming characteristic amyloid fibrils.•LQVVR might be a key segment for HCC aggregation into amyloid fibrils.•A model is proposed for HCC fibrillization.

Human cystatin C (HCC) is a low molecular weight member of the cystatin family (type2). HCC consists of 120 amino acids. Normally it is an inhibitor of cysteine proteases, but in pathological conditions it forms amyloid fibrils in brain arteries of young adults. An ‘aggregation-prone’ pentapeptide (47LQVVR51) was located within the HCC sequence using AmylPred, an ‘aggregation-prone’ peptide prediction algorithm developed in our lab. This peptide was synthesized and self-assembled into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, Attenuated Total Reflectance Fourier-Transform Spectroscopy and Congo red staining studies reveal. Thus, the 47LQVVR51 peptide seems to have an important role in HCC fibrillization.