Structure and Internal Dynamics of Calcitonin Family Peptides: Implications for Amyloid Formation

Abstract

The calcitonin peptide (Ct) family comprises the intrinsically disordered proteins amylin (IAPP), calcitonin gene-related peptide (CGRP), calcitonin, and adrenomedullins. These are genetically and structurally related hormone peptides that are able to bind to each other's receptors, though with varying degrees of affinity. Some of these peptides form amyloid fibers, while others do not. 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 laser spectroscopy technique to measure transient tertiary contact formation. This technique reveals information on the structure and internal dynamics of IDPs. We compare members of the Ct family which differ in hydrophobicity and net charge, and study the effect of proline mutations on contact formation rates. We find that functionally required, conserved sequence elements play an important role in determining the structure, internal dynamics and aggregation properties of these peptides.