Heart failure is the leading cause of mortality in the United States, but the structural mechanisms behind this disease are not well understood, so there are no effective therapies to treat it. A key molecular dysfunction in heart failure involves impaired Ca2+ transport during diastole, usually associated with insufficient calcium pump (sarcoplasmic reticulum Ca2+-ATPase, SERCA) expression and unaltered levels of phospholamban (PLB), an endogenous protein that inhibits SERCA in the heart. Abnormally low SERCA activity due to PLB inhibition is a hallmark of heart failure, so determining the mechanisms for SERCA activation and regulation is urgently needed to understand the molecular basis of the disease, and to design effective approaches to restore SERCA function in the failing heart. These mechanisms are complex, requiring structural changes and interdomain communication pathways that are difficult to determine experimentally. Since complete experimental characterization of these mechanisms is likely to remain an intractable problem, we propose to use molecular modeling and simulations tools to detect mechanisms for SERCA activation and regulation with high spatiotemporal resolution, and to discover of small-molecule SERCA activators.
Three Specific Aims will be pursued in this project: (1) Map ligand-induced structural changes associated with SERCA activation. (2) Determine the molecular mechanisms for PLB regulation of SERCA. (3) Perform virtual search of hits that activate SERCA by targeting the SERCA-PLB interface. For this project, we use skeletal SERCA1a as starting point to test our hypotheses because crystal structures have been obtained only for this isoform. The structural results from our studies are directly applicable to cardiac SERCA2a because there are no significant differences in the function of both isoforms, including regulation by PLB. The simulation work will be closely coupled to experiments through collaborations; experimental data will serve to complement the hypotheses tested by our simulations, and the high-resolution predictions from our simulations will provide new hypotheses for experimentalists to test in the lab. This project has great potential for pushing important frontiers in our understanding of the molecular mechanisms for SERCA function in cardiac health and disease, and to advance heart failure therapies through the discovery of SERCA activators.
Heart failure is the leading cause of mortality in the United States, but the structural mechanisms behind this disease are not well understood, so there are no effective therapies to treat it. This project investigates the molecular mechanisms and regulation of the calcium pump, an attractive therapeutic target whose reduced activity is central to heart failure pathogenesis. These studies will be crucial to understand the structural basis of heart failure, and to advance treatment through the discovery of calcium pump therapeutics.
| Fernández-de Gortari, Eli; Espinoza-Fonseca, L Michel (2018) Structural basis for relief of phospholamban-mediated inhibition of the sarcoplasmic reticulum Ca2+-ATPase at saturating Ca2+ conditions. J Biol Chem 293:12405-12414 |
| Espinoza-Fonseca, L Michel (2017) The Ca2+-ATPase pump facilitates bidirectional proton transport across the sarco/endoplasmic reticulum. Mol Biosyst 13:633-637 |
| Fernández-de Gortari, Eli; Espinoza-Fonseca, L Michel (2017) Preexisting domain motions underlie protonation-dependent structural transitions of the P-type Ca2+-ATPase. Phys Chem Chem Phys 19:10153-10162 |
| Autry, Joseph M; Thomas, David D; Espinoza-Fonseca, L Michel (2016) Sarcolipin Promotes Uncoupling of the SERCA Ca2+ Pump by Inducing a Structural Rearrangement in the Energy-Transduction Domain. Biochemistry 55:6083-6086 |
