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

Ottl J, Battistuta R, Pieper M, Tschesche H, Bode W, Kuhn K, Moroder L (1996)
FEBS LETTERS 398(1): 31-36.

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Abstract
A heterotrimeric collagen peptide was designed and synthesized which contains the collagenase cleavage site (P-4-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 (alpha 1 alpha 2 alpha 1') was found to exhibit a typical collagen-like CD spectrum at room temperature and a melting temperature (T-m) 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 alpha 1' chain, Tn contrast, opposite digestion rates were measured with the catalytic Phe(79)-MMP-8 domain of HNC. Moreover, the full-length enzyme exhibits K-m values of 5 mu M and 1 mM for the heterotrimer and the single alpha 1' chain, respectively, which compare well with those reported for collagen type I (similar to 1 mu M), gelatine (similar to 10 mu M) and for octapeptides of the cleavage sequence (greater than or equal to 1 mM), The high affinity of the MMP-8 for the triple-helical heterotrimer and the fast digestion of this collagenous peptide confirm the decisive role of the hemopexin domain in recognition and possibly, partial unfolding of collagen.
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Ottl J, Battistuta R, Pieper M, et al. Design and synthesis of heterotrimeric collagen peptides with a built-in cystine-knot - Models for collagen catabolism by matrix-metalloproteases. FEBS LETTERS. 1996;398(1):31-36.
Ottl, J., Battistuta, R., Pieper, M., Tschesche, H., Bode, W., Kuhn, K., & Moroder, L. (1996). Design and synthesis of heterotrimeric collagen peptides with a built-in cystine-knot - Models for collagen catabolism by matrix-metalloproteases. FEBS LETTERS, 398(1), 31-36.
Ottl, J., Battistuta, R., Pieper, M., Tschesche, H., Bode, W., Kuhn, K., and Moroder, L. (1996). Design and synthesis of heterotrimeric collagen peptides with a built-in cystine-knot - Models for collagen catabolism by matrix-metalloproteases. FEBS LETTERS 398, 31-36.
Ottl, J., et al., 1996. Design and synthesis of heterotrimeric collagen peptides with a built-in cystine-knot - Models for collagen catabolism by matrix-metalloproteases. FEBS LETTERS, 398(1), p 31-36.
J. Ottl, et al., “Design and synthesis of heterotrimeric collagen peptides with a built-in cystine-knot - Models for collagen catabolism by matrix-metalloproteases”, FEBS LETTERS, vol. 398, 1996, pp. 31-36.
Ottl, J., Battistuta, R., Pieper, M., Tschesche, H., Bode, W., Kuhn, K., Moroder, L.: Design and synthesis of heterotrimeric collagen peptides with a built-in cystine-knot - Models for collagen catabolism by matrix-metalloproteases. FEBS LETTERS. 398, 31-36 (1996).
Ottl, J, Battistuta, R, Pieper, M, Tschesche, Harald, Bode, W, Kuhn, K, and Moroder, L. “Design and synthesis of heterotrimeric collagen peptides with a built-in cystine-knot - Models for collagen catabolism by matrix-metalloproteases”. FEBS LETTERS 398.1 (1996): 31-36.
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