Protein complex: The matter of the heart

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  • Published: Oct 15, 2014
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Protein complex: The matter of the heart

Cardiac killer

Nuclear magnetic resonance (NMR) spectroscopy is offering important clues to the underlying protein changes that are present in heart failure and might offer up new targets for therapeutic agents and treatments to protect us against one of the biggest killers in the developed world. Credit Hwang, Sykes et al/PNAS

Nuclear magnetic resonance (NMR) spectroscopy is offering important clues into how changes in protein structure present in heart failure impact the pumping action of the heart, suggesting new strategies for treating one of the biggest killers in the developed world.

The end stage of heart disease is heart failure, in which the heart can no longer pump sufficient blood to satisfy the body's needs. Patients become progressively short of breath as the condition worsens, and they also begin to accumulate fluid in the legs and lungs, making it even more difficult to breathe. Normally, there is a carefully regulated balance between contraction and relaxation in the healthy heart. When contraction is impaired we see systolic heart failure; impaired relaxation on the other hand leads to diastolic heart failure. Systolic heart failure is most commonly caused by ischemia due to atherosclerotic coronary artery disease. Scientists do not know what causes diastolic heart failure. While both forms of heart failure - diastolic and systolic - are very different in their causes, they are similar in terms of overall prevalence, the symptoms they cause, and ultimately, mortality.

Phosphorylation furore

In heart failure, one critical change that occurs is an increase in "calcium sensitivity". Calcium ions are pumped in and out of the muscle cell with each heartbeat, turning contractions on and off. In healthy people, the protein troponin complex is highly phosphorylated, but in heart failure, it becomes dephosphorylated. This molecular change increases calcium sensitivity (the intracellular calcium concentration at which troponin triggers contraction). When the calcium sensitivity increases, contractility increases, but at a price: the relaxation of the heart becomes slower. Writing in the journal Proceedings of the National Academy of Sciences, Peter Hwang, Brian Sykes and colleagues at the University of Alberta's Faculty of Medicine & Dentistry explain how they have used multinuclear multi- dimensional solution NMR spectroscopy to study the behaviour of the troponin complex and in particular how phosphorylation impacts calcium sensitivity.

“Although phosphorylation of troponin has been known to be an important regulatory mechanism since 1976, the atomic-level explanation was a mystery,” explains Hwang, the lead author in the study. “It turns out that the phosphorylated region of troponin is an intrinsically disordered region (IDR). This means that it cannot be studied by the usual method for obtaining atomic level structures, X-ray crystallography.”

Troponin complex

“We were able to use NMR to show that electrostatic interactions within the unphosphorylated troponin complex keep it in an optimal alignment to trigger contraction. The introduction of negative groups through phosphorylation disrupts this electrostatic interaction, favouring relaxation.”

"Scientists believed that the dephosphorylation of troponin I seen in heart failure somehow caused the troponin complex to become less functional. Actually, the change brings it into the optimal alignment to trigger contraction. The heart has other mechanisms of regulating calcium sensitivity that probably also act by stabilizing or disrupting this arrangement."

“The heart is a constantly moving machine. At the molecular level, this means that proteins continually switch between a contracted and a relaxed state. NMR is the perfect method for studying the dynamic nature of these proteins.”

Hwang and colleagues hope to extend their work to other components of the cardiac contractile apparatus. The troponin complex is part of the thin filament of the sarcomere, which also includes tropomyosin and actin. “In all of these components, there must be a contracted state and a relaxed state. Either one of these can be destabilized by a mutation or post-translational modification, having a tremendous impact on the mechanical function of the heart. We are currently trying to develop drugs so that doctors can intentionally shift this balance to treat heart failure.”

Related Links

Proc Natl Acad Sci 2014, 111, 14412-14417: "The cardiac-specific N-terminal region of troponin I positions the regulatory domain of troponin C"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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