Scientists identify a key mechanism regulating a protein required for muscle and heart function

January 12, 2018, Centro Nacional de Investigaciones Cardiovasculares
Scientists identify a key mechanism regulating a protein required for muscle and heart function
Three-dimensional structure of one of the more than 100 immunoglobulin domains in titin. A disulfide bond is highlighted in red between two cysteines brought into proximity by the protein folding. When the immunoglobulin domain is subject to mechanical force, as during muscle stretching or in the diastolic phase of heart contraction, the domain opens up but is prevented from completely unfolding by the presence of the disulfide bond. Credit: CNIC

Scientists at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and Columbia University in New York have discovered an important mechanism in the regulation of a protein that plays an essential role in the function of skeletal muscle and the heart. The study, published today in Nature Communications and coordinated by CNIC researcher Jorge Alegre-Cebollada, describes a new mechanism in the regulation of the elasticity of the giant protein titin. Titin, explained Alegre-Cebollada, is a key protein in the functioning of striated muscles throughout the body, particularly in the heart: "the proof of this is that mutations in the titin gene are a common cause of diseases affecting the muscles of the body and the heart."

Titin is the largest in the human body and as such has a multitude of functions. According to Jorge Alegre-Cebollada, "in simple terms we can think of titin as a 'molecular spring' that allows muscle cells to contract in synchrony." However, it is not a simple spring, and the many mechanisms that determine titin elasticity include the unfolding of specific regions in its structure called immunoglobulin domains. In all, titin elasticity is determined by the concerted action of more than 100 immunoglobulin domains within the protein.

Using bioinformatic and structural biology approaches, the research team found that the immunoglobulin domains have a high cysteine content. This amino acid confers special properties. Jorge Alegre-Cebollada explained that "when 2 cyteines in a protein come close to one another, they can form a chemical link between different parts of the polypeptide chain called a disulfide bond." The researchers observed that many of the immunoglobulin domains in titin form disulfide links and that the cysteines participating in them can change dynamically, a process called isomerization. "The most interesting finding was that the formation and isomerization of causes major changes in the elastic properties of titin."

The formation of disulfide bonds is an example of a broader class of biochemical transformations known as reduction-oxidation (redox). It has long been known that many disease processes affecting the , including myocardial infarction, involve sudden and drastic changes in the redox state of the heart muscle.

Dr. Alegre-Cebollada's group is currently investigating how our cells modify the redox state as a mechanism to modulate skeletal and heart activity and how different diseases can interfere with the mechanical action of the protein, resulting in loss of functionality. Alegre-Cebollada concludes, "Our mechanical findings were made possible by reconstituting contractile systems in vitro. While we have learned a lot through this approach, the challenge now is to understand how these basic principles operate in a living organism. This is the focus of our current research, using a multidisciplinary approach that combines advanced techniques in physiology, biology, and biochemistry."

The study is the result of a collaboration between Dr. Alegre-Cebollada and Professor Julio Fernández at Columbia University. Professor Fernández is a pioneer in the development of single-molecule biophysical techniques for investigating the mechanical properties of proteins, and his collaboration with Dr. Alegre-Cebollada has made it possible to describe the biochemical regulation of protein mechanics.

Explore further: Researchers discover reversible mechanism that increases muscle elasticity

More information: David Giganti et al, Disulfide isomerization reactions in titin immunoglobulin domains enable a mode of protein elasticity, Nature Communications (2018). DOI: 10.1038/s41467-017-02528-7

Related Stories

Researchers discover reversible mechanism that increases muscle elasticity

March 13, 2014
How does yoga improve your flexibility? In the Mar 13 cover story of Cell, Columbia University biological sciences professor Julio Fernandez and team report the discovery of a new form of mechanical memory that adjusts the ...

Introducing titin, the protein that rules our hearts

November 14, 2017
Although scientists have long speculated that a protein named titin measures thick filaments—the proteins that make muscles contract—no one has been able to provide evidence to support their theories.

A trigger for muscular diseases

January 27, 2014
A University of Arizona doctoral candidate has shown for the first time that genetic mutations in the titin gene can cause skeletal muscle myopathy, a disease in which muscle fibers do not function properly, resulting in ...

Enzyme CaM kinase II relaxes muscle cells: Researchers find overactive enzyme in failing hearts

January 17, 2013
A certain enzyme, the CaM kinase II, keeps the cardiac muscle flexible. By transferring phosphate groups to the giant protein titin, it relaxes the muscle cells. This is reported by researchers led by Prof. Dr. Wolfgang Linke ...

Researcher studies protein's link to heart disease

June 18, 2013
(Medical Xpress)—The largest protein known to exist in the human body functions as a molecular spring, and University of Arizona researchers are gaining new insights into its role in heart disease.

Recommended for you

Too liberal use of oxygen increases risk of death in acutely ill adult patients

April 26, 2018
McMaster University researchers have found there is such a thing as too much oxygen for acutely ill adults.

The complicated biology of garlic

April 26, 2018
Researchers today generally agree that eating garlic, used for thousands of years to treat human disease, can reduce the risk of developing certain kinds of cancers, cardiovascular disease, and type 2 diabetes. Nevertheless, ...

CRISPR-based diagnostic SHERLOCK optimized for rapid use during viral outbreaks

April 26, 2018
In a paper published today in Science, researchers at Broad Institute of MIT and Harvard report a new tool that engineers the CRISPR-based diagnostic SHERLOCK for rapid outbreak response. The updates to SHERLOCK, which was ...

Noninvasive brain tumor biopsy on the horizon

April 26, 2018
Taking a biopsy of a brain tumor is a complicated and invasive surgical process, but a team of researchers at Washington University in St. Louis is developing a way that allows them to detect tumor biomarkers through a simple ...

Lab-on-a-chip delivers critical immunity data for vulnerable populations

April 25, 2018
For millions of displaced people around the world—many of them refugees, living in temporary shelters under crowded conditions—an outbreak of disease is devastating. Each year, the measles virus kills more than 134,000 ...

Want new medicines? You need fundamental research

April 25, 2018
Would we be wise to prioritize "shovel-ready" science over curiosity-driven, fundamental research programs? Would that set the stage for the discovery of more new medicines over the long term?

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.