title: Exploring the 'aggregation-prone' core of human Cystatin C: A structural study.
abstract: Amyloidogenic proteins like human Cystatin C (hCC) have been shown to form dimers and oligomers by exchange of subdomains of the monomeric proteins. Normally, the hCC monomer, a low molecular type 2 Cystatin, consists of 120 amino acid residues and functions as an inhibitor of cysteine proteases. The oligomerization of hCC is involved in the pathophysiology of a rare form of amyloidosis namely Icelandic hereditary cerebral amyloid angiopathy, in which an L68Q mutant is deposited as amyloid in brain arteries of young adults. In order to find the shortest stretch responsible to drive the fibril formation of hCC, we have previously demonstrated that the LQVVR peptide forms amyloid fibrils, in vitro (Tsiolaki et al., 2015). Predictions by AMYLPRED, an amyloidogenic determinant prediction algorithm developed in our lab, led us to synthesize and experimentally study two additional predicted peptides derived from hCC. Along with our previous findings, in this work, we reveal that these peptides self-assemble, in a similar way, into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy and Congo red staining studies have shown. Further to our experimental results, all three peptides seem to have a fundamental contribution in forming the "aggregation-prone" core of human Cystatin C.
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: etsiolaki@biol.uoa.gr.
authors.forename: Paraskevi L
authors.initials: PL
authors.lastname: Tsiolaki
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: nlouros@biol.uoa.gr.
authors.forename: Nikolaos N
authors.initials: NN
authors.lastname: Louros
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: shamodr@biol.uoa.gr.
authors.forename: Stavros J
authors.initials: SJ
authors.lastname: Hamodrakas
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: veconom@biol.uoa.gr.
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Iconomidou
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry; D000686:Amyloidosis / Q000235:genetics; D055316:Cystatin C / Q000737:chemistry*; D019281:Dimerization; D006801:Humans; D008854:Microscopy, Electron / Q000379:methods; D008969:Molecular Sequence Data; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D000682:Amyloid; D055316:Cystatin C
keywords: 3D-domain swapping; Amyloid fibrils; Hereditary Cystatin C Amyloid Angiopathy; Human Cystatin C; Stefin; ‘Aggregation-prone’ peptides