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Proteins need to be tough: many respond to mechanical forces, which means that they bounce back from repeated cycles of forces which physically alter their structure, stretching or squishing them out of shape. Now a new paper led by Drs Justin Benesch and Katja Gehmlich has identified interactions which might stop a protein found in the heart from literally overextending itself.

“The heart is an organ which undergoes quite a lot of mechanical stress,” said Dr Gehmlich from the Radcliffe Department of Medicine. “In order to physically pump blood around the body, the heart changes its size and shape a lot during each heart beat, which means that proteins that make up heart muscles probably experience the largest mechanical forces in the body.

This means that proteins in the heart need to detect and respond to physical forces, but still retain their structural integrity.”

Filamin C

The team of Oxford University researchers and their European collaborators focussed on a protein known as filamin C, which is a key protein in many signalling pathways. By cross-linking with the protein actin to create complex three-dimensional networks, filamin C also helps cells move by participating in formation of the cellular ‘skeleton’. Equally important, filamin C is also a key part of the contractile apparatus in muscles.

People with mutations in the gene that makes filamin C can have serious malfunctions, either in the heart or in skeletal muscle. Filamin C’s function in muscle suggests that it would need to detect and respond to physical forces.

The research team used techniques spanning the range from looking at interactions at the atomic to tissue level, to track how filamin C might be responding to stress, and how its interaction with a ‘chaperone’ protein called HspB1 might protect it from being over-stretched and damaged.

The study’s first author, Miranda Collier from the Department of Chemistry at Oxford University said: “We applied various structural biology techniques to analyse both proteins separately and together, to understand how they interact with each other“.

Dr Justin Benesch, also from the Department of Chemistry, adds: “Our gas phase collision experiments can mimic the way filamin C is pulled to its full extent by an external force and help us understand how this process is changed by the presence of HspB1.”

The team thinks that this interaction between HspB1 and filamin C might be protecting filamin C from damage. Combined with previous work, they suggest that there might be a tiered set of mechanisms that protect this crucial heart muscle protein, each active at a different tension – the HspB1 mechanism appears to kick in at high mechanical stress, when filamin C is at risk of being stretched so much that it may not function properly.

The team now plans to explore the potentially protective activities of HspB1 for the heart further in model systems for heart failure, a common disease associated with high mortality and high costs for health care systems.

Read the full paper at Science Advances.

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