News

First study showing how protein fine-tunes the heart



24 November 2008

Dr Andrew Whitten, Dr Cy Jeffries and Professor Jill Trewhella, from the School of Molecular and Microbial Biosciences, University of Sydney, with Samantha Harris, from the University of California, USA, have the first data clearly showing how a protein in heart muscle cells works to maintain regular heart function.

New research shows for the first time how cardiac myosin-binding protein C (blue, with domains C0, C1, m and C2 marked) binds to actin (red), and maintains regular heart function.
New research shows for the first time how cardiac myosin-binding protein C (blue, with domains C0, C1, m and C2 marked) binds to actin (red), and maintains regular heart function.

The research, published in the Proceedings of the National Academy of Sciences, USA, on 25 November 2008, shows how this cardiac protein interacts with actin - one of the two filament-forming muscle proteins (the other is myosin) that slide past each other to create the rhythmic contraction and relaxation that causes our heart to beat.

"Understanding the structure of this heart protein - called cardiac myosin-binding protein C - and how it attaches to actin, gives us an insight into how it actually works to modulate heart contractions," explained Professor Jill Trewhella.

"There's a lot of interest in cardiac myosin-binding protein C, because of its influence on fine-tuning heart muscle contractions and its links to familial hypertrophic cardiomyopathy - an inherited cardiac disorder that affects one in 500 adolescents and young adults.

"Young people with familial hypertrophic cardiomyopathy have a gradual thickening of the ventricle walls of their hearts and a correlated increase in the risk of heart failure," said Professor Trewhella.

However, the precise molecular mechanisms by which cardiac myosin-binding protein C influences actin and myosin interactions have not been fully understood.

Cardiac myosin-binding protein C, known as an 'accessory protein' in the muscle cells that keep our hearts beating, is a long molecule made up of eleven segments, called domains, arranged like beads on a string.

Using neutron scattering to examine the structure of cardiac myosin-binding protein C when bound to actin, the team found the specific domains of the protein that bind to and stabilise actin filaments.

"It turns out there are two domains of cardiac myosin-binding protein C that bind to actin - the C0 and C1 domains that are at one end of the molecule. Domains at the opposite end are attached to myosin," explained Professor Trewhella.

"This is a real first - it's the first direct structural evidence that clearly shows how cardiac myosin-binding protein C stabilises actin filaments. We've not only found the particular domains of the protein that bind to actin, but where they bind and how they are positioned to modulate the interactions between actin and myosin and hence the contractile cycle," said Professor Trewhella.

"Dr Andrew Whitten and Dr Cy Jeffries, two postdoctoral research fellows in the School of Molecular and Microbial Biosciences, University of Sydney, performed the research and analysed the data from experiments which the team had designed. Andrew also developed a new 2D atom modeling program - a new analytic tool to examine the data.

"It's great to see two young scientists early in their career produce this successful and exciting research that will help inform us of the molecular basis for a devastating disease," said Professor Trewhella.


Contact: Katynna Gill

Phone: 02 9351 6997

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