Design and synthesis of heterotrimeric collagen peptides with a built-in cystine-knot. Models for collagen catabolism by matrix-metalloproteases

FEBS Letters
J OttlLuis Moroder

Abstract

A heterotrimeric collagen peptide was designed and synthesized which contains the collagenase cleavage site (P4-P'9/10) of type I collagen linked to a C-terminal cystine-knot, and N-terminally extended with (Gly-Pro-Hyp)5 triplets for stabilization of the triple-helical conformation. By employing a newly developed regioselective cysteine pairing strategy based exclusively on thiol disulfide exchange reactions, we succeeded in assembling in high yields and in a reproducible manner the triple-stranded cystine peptide. While the single chains showed no tendency to self-association into triple helices, the heterotrimer (alpha1 alpha2 alpha1') was found to exhibit a typical collagen-like CD spectrum at room temperature and a melting temperature (Tm) of 33 degrees C. This triple-helical collagen-like peptide is cleaved by the full-length human neutrophil collagenase (MMP-8) at a single locus fully confirming the correct raster of the heterotrimer. Its digestion proceeds at rates markedly higher than that of a single alpha1' chain. In contrast, opposite digestion rates were measured with the catalytic Phe79-MMP-8 domain of HNC. Moreover, the full-length enzyme exhibits Km values of 5 microM and 1 mM for the heterotrimer and the single...Continue Reading

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Citations

Apr 1, 1999·Journal of Peptide Science : an Official Publication of the European Peptide Society·J OttlL Moroder
Apr 17, 2001·Biopolymers·A V PersikovB Brodsky
Sep 14, 2002·Biopolymers·Janelle L Lauer-FieldsGregg B Fields
Jan 12, 2010·Journal of the American Chemical Society·Lesley E RussellJeffrey D Hartgerink
Sep 8, 2011·The Journal of Biological Chemistry·Trista K RobichaudGregg B Fields
Oct 27, 2007·Antioxidants & Redox Signaling·Cyril BoulègueLuis Moroder
Nov 20, 2002·Biological Chemistry·Janelle L Lauer-Fields, Gregg B Fields
Mar 6, 2010·Organic & Biomolecular Chemistry·Gregg B Fields
Jan 29, 2016·The Journal of Physical Chemistry. B·Chu-Harn Chiang, Jia-Cherng Horng
Jul 23, 2008·Journal of Molecular Biology·Paul S Nerenberg, Collin M Stultz
Mar 23, 2005·Biochimie·Carine LombardJean Wallach
Jun 23, 2009·Drug and Chemical Toxicology·Sohail EjazChae Woong Lim
Aug 1, 2015·Biochemistry·Avanish S ParmarVikas Nanda
May 8, 2016·Journal of Computational Biology : a Journal of Computational Molecular Cell Biology·Yuchao PanWei Xu
Mar 25, 2011·Journal of the American Chemical Society·Lesley E R O'LearyJeffrey D Hartgerink
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