Abstract
Calcitonin gene-related peptide (CGRP) is an intrinsically disordered, 37 residue neuropeptide that acts as a potent vasodilator, which is of considerable interest in migrane research. It is a member of the calcitonin peptide (Ct) family, together with amylin, calcitonin and adrenomedullin. These are genetically and structurally related intrinsically disordered hormone peptides that are able to bind to each other’s receptors, though with varying degrees of affinity. They contain highly conserved sequence elements that have been experimentally shown to affect the secondary structural preferences of these peptides. The effect of such conserved elements on tertiary structure has not been experimentally explored to the same extent. Detecting tertiary structural properties of IDPs is considerably more challenging due to fast reconfigurations of the backbone over a wide range of possible conformations. High resolution time-resolved techniques are needed.We use a nanosecond-resolved spectroscopic technique based on tryptophan triplet quenching by cystine to detect tertiary contact formation in CGRP under varying solvent and temperature conditions. Using this technique, Vaiana et al.1 have previously shown that conserved structural elements of amylin induce compact states characterized by short end-to-end distances, and that compaction is not driven by hydrophobic side-chains. Using triplet quenching we explore the effect of these conserved elements on the conformation and dynamics of CGRP, a peptide with higher mean hydrophobicity and net charge per residue than amylin. We discuss our findings in relation to secondary structural preferences of these peptides and discuss their possible functional role.Footnote1 Vaiana S.M. et al. Biophys. J. 97 2009.
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