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Gary Lorigan awarded $1.5M for membrane protein research


A molecular graphical view of the membrane protein phospholamban.
Gary Lorigan (chemistry and biochemistry) has received a nearly $1.4 million NIH RO1 grant from the National Institute of General Medical Sciences (NIGMS, part of the National Institutes of Health) for a study of new spectroscopic methods for probing the structure of membrane proteins. He has also been awarded a $121,000 grant from the American Heart Association for a study of the structure of mutated forms of the membrane protein phospholamban, which are directly related to heart disease.

Membrane proteins - which make up approximately one-third of the total number of proteins - are essential for many important functions of biological systems. They are vital to health, and specific defects are associated with many known diseases, according to the National Institutes of Health (NIH). Despite the abundance and importance of membrane proteins - which comprise more than half of human drug targets - little structural information about them exists. Located in the oily two-layer membrane that holds cells together, they are not water-soluble and are more difficult to study than soluble proteins.

While the rate of soluble protein structure determination has increased rapidly in the last decade, slower progress in determining the structure of membrane proteins "demonstrates that solving membrane protein structures is feasible albeit difficult, so innovative approaches are clearly still needed," according to the NIH.

Lorigan and his research group responded to this need by developing a new method for probing the structural properties of membrane proteins using electron paramagnetic resonance (EPR) spectroscopy and solid-state nuclear magnetic resonance (NMR) spectroscopy. Their initial work was highlighted last year by the journal Nature Methods as a "promising new structural biology tool."

With the NIGMS award, Lorigan will continue research on this method development, using the integral membrane protein phospholamban. New EPR spectroscopic methods will be developed to probe the structures of integral membrane proteins; results will be directly compared with results using with NMR spectroscopic data.

"We feel that this new approach will move the field forward so that researchers can more easily and inexpensively determine the structural topology of integral membrane proteins using spin-label EPR spectroscopy," says Lorigan.

Since no crystal structures of the membrane protein phospholamban have been published, Lorigan's work on the protein can only be accomplished by using state-of-the art solid-state NMR spectroscopic techniques. Phospholamban (PLB) is essential for the regulation of the flow of calcium ions in cardiac muscle cells, enabling the cardiac muscle to relax after a contraction. Two mutants of PLB have been shown to be directly related to heart failure.

Lorigan's research aims to determine the structural and dynamic properties of these important mutants. Structural data may lead to the design of appropriate drugs targeted to relieve the PLB inhibition of the calcium-ATPase pump and improve function in heart disease, says Lorigan.


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