Synthesis and physicochemical studies of amyloidogenic hexapeptides derived from human cystatin C

Emilia Iłowska , Justyna Sawicka , Aneta Szymańska

Abstract

Human cystatin C (hCC) is a low molecular mass protein that belongs to the cystatin superfamily. It is an inhibitor of extracellular cysteine proteinases, present in all human body fluids. At physiological conditions, hCC is a monomer, but it has a tendency to dimerization. Naturally occurring hCC mutant, with leucine in position 68 substituted by glutamine (L68Q), is directly involved in the formation of amyloid deposits, independently of other proteins. This process is the primary cause of hereditary cerebral amyloid angiopathy, observed mainly in the Icelandic population. Oligomerization and fibrillization processes of hCC are not explained equally well, but it is proposed that domain swapping is involved in both of them. Research carried out on the fibrillization process led to new hypothesis about the existence of a steric zipper motif in amyloidogenic proteins. In the hCC sequence, there are 2 fragments which may play the role of a steric zipper: the loop L1 region and the C‐terminal fragment. In this work, we focused on the first of these. Nine hexapeptides covering studied hCC fragment were synthesized, and their fibrillogenic potential was assessed using an array of biophysical methods. The obtained results showed that the studied hCC fragment has strong profibrillogenic propensities because it contains 2 fragments fulfilling the requirements for an effective steric zipper located next to each other, forming 1 super‐steric zipper motif. This hCC fragment might therefore be responsible for the enhanced amyloidogenic properties of dimeric or partially unfolded hCC.
Author Emilia Iłowska (FCh / DBCh / LMCh)
Emilia Iłowska,,
- Laboratory of Medical Chemistry
, Justyna Sawicka (FCh / DBCh / LMCh)
Justyna Sawicka,,
- Laboratory of Medical Chemistry
, Aneta Szymańska (FCh / DBCh / LMCh)
Aneta Szymańska,,
- Laboratory of Medical Chemistry
Journal seriesJournal of Peptide Science, ISSN 1075-2617, (A 20 pkt)
Issue year2018
Vol24
No4-5
Pages1-11
Keywords in Englishamyloid fibril, human cystatin C, peptide, physicochemical studies, steric zipper
DOIDOI:10.1002/psc.3073
URL https://doi.org/10.1002/psc.3073
Languageen angielski
Score (nominal)20
ScoreMinisterial score = 20.0, 27-04-2018, ArticleFromJournal
Ministerial score (2013-2016) = 20.0, 27-04-2018, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 1.972 (2) - 2016=1.709 (5)
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