BIOPHYSICS SEMINAR Featuring Giuseppe Melacini “Tapping the Translation Potential of cAMP-Signalling and Amyloid Inhibition using NMR”

“Tapping the Translation Potential of cAMP-Signalling and Amyloid Inhibition using NMR”

Abstract

Our work focuses on the use of NMR spectroscopy to understand two fundamental processes in humans: intracellular cAMP-dependent conformational switches and extracellular amyloid inhibition by plasma proteins. Eukaryotic cAMP-binding domains (CBDs) control multiple cellular functions (e.g. phosphorylation by protein kinase A - PKA, guanine exchange by the exchange protein directly activated by cAMP – EPAC, and ion channel gating in the hyperpolarization and cyclic-nucleotide modulated ion channels - HCN). Hence, the translational potential arising from the manipulation of cAMP-dependent signaling pathways is high.   However, the ubiquity of eukaryotic CBDs also poses a challenge in terms of selectivity.  Before the full translational potential of cAMP-signalling can be tapped, it is critical to understand the structural basis for selective cAMP agonism and antagonism, which is being deciphered through recent NMR approaches developed in our laboratory [1-4]. The comparative NMR analyses of multiple eukaryotic CBDs in PKA, EPAC and HCN is expected to facilitate the development of selective CBD effectors that may serve as drug leads for the treatment of multiple cardiovascular diseases.  As time allows, we will also show how recent NMR developments have led to the elucidation of the mechanisms underlying the extracellular chaperone function of plasma proteins, which are effective inhibitors of self-association for the Ab peptide linked to Alzheimer’s disease [5].