Scientists have found the role of two proteins in the functioning of the heart. The results could help better design targeted strategies to treat certain cardiomyopathies. The results are out in PNAS.
The heart works using tiny muscle filaments, and two main steps control how they interact: first calcium signals cause changes in the thin filament (actin), allowing it to connect with myosin motors. Then myosin motors on the thick filament switch from “off” (inactive) to “on” (active), so they can pull on actin and create force and shortening. The thick filament can sense how much force is needed and adjust how many motors to turn on, but scientists are still figuring out exactly how this works.
Cardiomyopathies take place when these mechanisms regulating the contraction-relaxation cycle of the heart malfunction. This is due to mutations in the contractile proteins (myosin and actin) but also in accessory proteins (Myosin-binding protein-C and titin). Broadly, MyBP-C and titin ensure together that the heart contracts effectively while maintaining responsiveness to changes in demand.
A team from the University of Firenze (Italy) used small-angle X-ray diffraction at the ESRF’s ID02 beamline back in 2017 and showed that, during muscle contraction, myosin motors move outward from the thick filament, enabling interaction with actin based on the load, which in the cardiac ventricle is the arterial pressure against which blood must be pumped (Reconditi et al. PNAS 2017). Evidence from other laboratories also suggested that thick filament activation is modulated by regulatory domains in the myosin motor itself and by accessory proteins like MyBP-C and titin. However, their specific function in cardiac performance was not known in detail.
Now the same team has found the role that MyBP-C and titin play in the functioning of the heart, at beamline ID02. “The beamline ID02 is ideal thanks to its camera length, so we can have the detector closer or further to the samples in a range from 0.5 to 31 m. This lets us explore the contractile proteins as well as the sarcomere, the unit cell of muscle, which is crucial for our research”, says Massimo Reconditi, scientist at the University of Firenze and corresponding author of the paper. “With EBS, thanks to its low divergence, we can observe on the same diffraction pattern a high number of reflections together with their fine structure”, he adds.
Read more on ESRF website
Image: Theyencheri Narayanan, scientist in charge of ID02, on the beamline.
Credit: S. Candé.