Functional dynamics in cyclic nucleotide signaling and amyloid inhibition

Abstract

It is now established that understanding the molecular basis of biological function requires atomic resolution maps of both structure and dynamics. Here, we review several illustrative examples of functional dynamics selected from our work on cyclic nucleotide signaling and amyloid inhibition. Although fundamentally diverse, a central aspect common to both fields is that function can only be rationalized by considering dynamic equilibria between distinct states of the accessible free energy landscape. The dynamic exchange between ground and excited states of signaling proteins is essential to explain auto-inhibition and allosteric activation. The dynamic exchange between non-toxic monomeric species and toxic oligomers of amyloidogenic proteins provides a foundation to understand amyloid inhibition. NMR ideally probes both types of dynamic exchange at atomic resolution. Specifically, we will show how NMR was utilized to reveal the dynamical basis of cyclic nucleotide affinity, selectivity, agonism and antagonism in multiple eukaryotic cAMP and cGMP receptors. We will also illustrate how NMR revealed the mechanism of action of plasma proteins that act as extracellular chaperones and inhibit the self-association of the prototypical amyloidogenic Aβ peptide. The examples outlined in this review illustrate the widespread implications of functional dynamics and the power of NMR as an indispensable tool in molecular pharmacology and pathology.

Keywords: Allostery; Amyloid; NMR; Signaling; cAMP.