Scientists at the National Center for Cardiovascular Research Carlos III (CNIC) and Columbia University have discovered a key mechanism in the regulation of a protein essential for muscle and heart function.
The work, published today in Nature Communications and coordinated by the CNIC researcher Jorge Alegre-Cebollada, described a new mechanism for regulating the elasticity of the giant protein titin.
Titin, Alegre-Cebollada explained, is a key protein for the functioning of our muscles in general and the heart in particular. “Proof of this is that mutations in the titin gene are frequent causes of myopathies and cardiomyopathies,” he said.
Titin is the largest protein present in humans and, therefore, has many functions. Simplifying it greatly, the researcher said, “we can describe it as a ‘molecular spring’, which allows the muscle cells to contract in sync.”
However, it is not a simple spring and one of several physical mechanisms that determine the elasticity of titin is the unfolding of certain parts of its structure, called immunoglobulin domains. There are more than one hundred titin domains, which concerted action determines the overall elasticity of this protein.
Using bioinformatics and structural biology techniques, the team realized that these immunoglobulin domains included a high content of a very special amino acid, cysteine. “In a protein, when two cysteines are close, can lead to a chemical bond between them, called disulfide bridge,” said Alegre-Cebollada.
The researchers found that many of the immunoglobulin domains of titin could establish these disulfide bridges; additionally, they observed it was possible that a dynamic exchange of these disulfide bridges were produced, called isomerization. “The interesting thing is that the presence and isomerization of disulfide bridges predicted drastic changes in the elastic properties of titin,” they said.
Further studies are needed
The formation of disulfide bridges from cysteines is part of a broader group of biochemical transformations called oxidation-reduction reactions (redox). For decades, it has been known that pathological processes such as a heart attack lead to drastic changes in the redox environment of the myocardium.
Currently, the team of Alegre-Cebollada is investigating how the modification of the titin’s redox state is used by the body as a mechanism of modulation of muscle and cardiac activity, and how various diseases can interfere with the mechanical activity of the protein, resulting in functional losses.
“The founded mechanisms we published were possible by reconstitution systems in vitro, from which we have learned a lot. The challenge now is to understand how these basic principles emerge in the living being, which is what we want through a multidisciplinary approach that includes the best of physiology, biology, physics and biochemistry,” Alegre-Cebollada concluded.