3D heart filaments devised resolving a 60

These proteins function in conjunction with each other to generate the contraction of the heart muscle. However, mutations in such proteins can lead to heart failure.

The scientists successfully solved the molecular structure of the main region of human cardiac filaments, particularly the part containing cMyBP-C (cardiac myosin-binding protein C).

The university statement clarified that the heart, consisting of billions of cells housing smaller structures called sarcomeres, serves as the fundamental unit of muscle. Inside each of these units contain numerous myosin filaments. 

“Each filament has roughly 2,000 molecules arranged in a really complicated structure that scientists have been trying to understand for decades,” stated Campbell. “We knew quite a lot about the individual molecules and people thought the myosins could be arranged in groups of six that were called crowns, but not much beyond that.”

Interactions between cardiac proteins

By explaining this structure of the heart, they were able to comprehend the interactions between these proteins and how they contribute to the normal functioning of the heart.

The discovery allowed scientists to create a new framework that interpreted various physiological and clinical observations related to heart health. The team of researchers produced single-particle 3D reconstructions of the cardiac thick filaments.

Campbell noted the study was important for discovering new drug therapies for heart disease, which Kentucky desperately needs. “It gives us a much better understanding of how the molecules in our hearts interact.”

The most intriguing finding of the research was three different types of crowns, according to Campbell. 

He added: “We think this means that heart muscle can be controlled more precisely than we had realized. We were also excited to see how myosin-binding protein-C, another protein that is linked to genetic heart disease, sits within the structure. It gives us a new level of information about how the molecules are arranged in the heart.”

Additionally, this structural knowledge holds promise for the development of potential therapeutic drugs targeting heart-related issues based on a deeper comprehension of these molecular interactions.

The study was published on November 1 in the journal Nature.

Study abstract:

Pumping of the heart is powered by filaments of the motor protein myosin that pull on actin filaments to generate cardiac contraction. In addition to myosin, the filaments contain cardiac myosin-binding protein C (cMyBP-C), which modulates contractility in response to physiological stimuli, and titin, which functions as a scaffold for filament assembly. Myosin, cMyBP-C and titin are all subject to mutation, which can lead to heart failure. Despite the central importance of cardiac myosin filaments to life, their molecular structure has remained a mystery for 60 years. Here we solve the structure of the main (cMyBP-C-containing) region of the human cardiac filament using cryo-electron microscopy. The reconstruction reveals the architecture of titin and cMyBP-C and shows how myosin’s motor domains (heads) form three different types of motif (providing functional flexibility), which interact with each other and with titin and cMyBP-C to dictate filament architecture and function. The packing of myosin tails in the filament backbone is also resolved. The structure suggests how cMyBP-C helps to generate the cardiac super-relaxed state; how titin and cMyBP-C may contribute to length-dependent activation; and how mutations in myosin and cMyBP-C might disturb interactions, causing disease. The reconstruction resolves past uncertainties and integrates previous data on cardiac muscle structure and function. It provides a new paradigm for interpreting structural, physiological and clinical observations, and for the design of potential therapeutic drugs.