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Protein Sci. 2012 Oct;21(10):1429-43. doi: 10.1002/pro.2129.

Calcium binding and allosteric signaling mechanisms for the sarcoplasmic reticulum Ca²+ ATPase.

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Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA.


The sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) is a membrane-bound pump that utilizes ATP to drive calcium ions from the myocyte cytosol against the higher calcium concentration in the sarcoplasmic reticulum. Conformational transitions associated with Ca²⁺-binding are important to its catalytic function. We have identified collective motions that partition SERCA crystallographic structures into multiple catalytically-distinct states using principal component analysis. Using Brownian dynamics simulations, we demonstrate the important contribution of surface-exposed, polar residues in the diffusional encounter of Ca²⁺. Molecular dynamics simulations indicate the role of Glu309 gating in binding Ca²⁺, as well as subsequent changes in the dynamics of SERCA's cytosolic domains. Together these data provide structural and dynamical insights into a multistep process involving Ca²⁺ binding and catalytic transitions.

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