Global regulation of the structure, dynamics, and function of the calcium sensor protein calmodulin revealed by paramagnetic NMR

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NIDDK	STRUCTBIO-1

* FARE Award Winner

Authors

• N Anthis
• M Clore

Abstract

Calmodulin (CaM) is the universal calcium sensor in eukaryotes, regulating the function of numerous proteins. Crystallography and NMR show that, in the absence of binding peptide, CaM-4Ca2+ exists in a predominantly open conformation with significant separation between its two domains, but clamps down upon target peptides to form a compact structure with extensive interdomain contacts. NMR studies on CaM-4Ca2+ have revealed a flexible linker and substantial interdomain motions, and one example of a closed CaM-4Ca2+ crystal structure exists. However, the formation of transient interdomain contacts has not been directly observed in solution. Here we use paramagnetic relaxation enhancement (PRE) to characterize transient closed states of free CaM that are too sparsely populated to observe by traditional NMR methods. We show that CaM samples a range of compact structures, populated at 5-10%, when not bound to peptide, and that Ca2+ dramatically alters the spatial distribution of these configurations in favor of states resembling the peptide-bound structure. These findings suggest that Ca2+ activates CaM not only through local structural changes within each domain but also through more global remodeling of interdomain interactions. These findings inform our understanding of Ca2+ signaling and illustrate the subtle interplay between conformational selection and induced fit.

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