UT Southwestern researchers characterize novel enzymes presenting potential in heart failure

Heart

The heart continuously pumps blood around the body to deliver oxygen and nutrient-rich blood to vital organs. Contraction of heart cells depends on the ability for filaments--myosin and actin--to interact with each other, shortening the length of each contractile unit and collectively the entire heart muscle.

The efficiency of contraction is thought to depend on the attachment (or removal) of a phosphate molecule to myosin filaments. Scientists at UT Southwestern Medical Center have identified and characterized two new enzymes that add phosphates to myosin--the results may lead to a new heart failure therapy.

The study was led by first author Audrey Chang, publishing their work in the journal Proceedings of the National Academy of Sciences.

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The team identified a new myosin kinase enzyme called MLCK4. This heart-specific enzyme attaches phosphate groups to myosins and it is the first enzyme to provide three-dimensional structure for the family of MLCK proteins. From learning about the structure, the team noted MLCK4 is missing a conserved regulatory section that would inhibit kinase activity--consistent with the biochemical findings that the protein is always turned on.

They found another heart-specific myosin kinase called MLCK3, this time with a regulatory section of the protein that allows increased activity--when a calcium modulator protein (called calmodulin) binds.

The process of adding or removing phosphate molecules is referred to as phosphorylation or dephosphorylation, respectively. The fine tuning of these two processes governs normal heart function; in animal studies it is known that too little phosphorylation causes heart failure--whilst too much phosphorylation can actually be protective. 

“The heart-specific expression of these kinases, and the linkage between low myosin phosphorylation and heart failure, makes targeting of these cardiac myosin kinases to improve cardiac function compelling,” said senior author of the study, James Stull.

- here’s the release

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