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Effect of 3-Hydroxyproline Residues on Collagen Stability

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posted on 30.04.2003, 00:00 by Cara L. Jenkins, Lynn E. Bretscher, Ilia A. Guzei, Ronald T. Raines
Collagen is an integral part of many types of connective tissue in animals, especially skin, bones, cartilage, and basement membranes. A fibrous protein, collagen has a triple-helical structure, which is comprised of strands with a repeating Xaa-Yaa-Gly sequence. l-Proline (Pro) and 4(R)-hydroxy-l-proline (4-Hyp) residues occur most often in the Xaa and Yaa positions. The 4-Hyp residue is known to increase markedly the conformational stability of a collagen triple helix. In natural collagen, a 3(S)-hydroxy-l-proline (3-Hyp) residue occurs in the sequence:  3-Hyp-4-Hyp-Gly. Its effect on collagen stability is unknown. Here, two host−guest peptides containing 3-Hyp are synthesized:  (Pro-4-Hyp-Gly)3-3-Hyp-4-Hyp-Gly-(Pro-4-Hyp-Gly)3 (peptide 1) and (Pro-4-Hyp-Gly)3-Pro-3-Hyp-Gly-(Pro-4-Hyp-Gly)3 (peptide 2). The 3-Hyp residues in these two peptides diminish triple-helical stability in comparison to Pro. This destabilization is small when 3-Hyp is in the natural Xaa position (peptide 1). There, the inductive effect of its 3-hydroxyl group diminishes slightly the strength of the interstrand 3-HypCO···HNGly hydrogen bond. The destabilization is large when 3-Hyp is in the nonnatural Yaa position (peptide 2). There, its pyrrolidine ring pucker leads to inappropriate mainchain dihedral angles and interstrand steric clashes. Thus, the natural regioisomeric residues 3-Hyp and 4-Hyp have distinct effects on the conformational stability of the collagen triple helix.

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