Cardiac secrets of the tarantula

In 2018, for outstanding achievements in original scientific research, our colleague, a biophysicist from Venezuela Raul Padrron (Raël Alejandro Padrón Crem), was elected a foreign member of the US National Academy of Sciences. Recently, PROCEEDINGS of the National Academy of Science (PNAS), his inauguration article in collaboration with scientists from different countries, is published, including our modest participation, dedicated to the study of molecular structural changes occurring during the contraction of the tarantula leg muscle [ 1 ]. Despite the exotic object of the study, this work not only allows us to understand the mechanisms of the work of various muscles of animals and humans, but also is directly related to some heart diseases.

Raul Padron was born in Karakas in Venezuela in 1950. He was also interested in science and began to work in a biochemical laboratory. He graduated from the University in Karakas with a degree in an electrical engineer, then he defended his master's work on biology with honors, and in 1979 he received a PhD in biophysics. In 1980-1983, he was a post -house in the molecular biology laboratory in Cambridge in the Hugh Huxley group (1924–2013), the classic of structural biology of muscles and one of the authors of the theory of sliding threads, on which modern ideas about the molecular mechanism of muscle contraction are based. About the years spent in Cambridge, and his teacher Hugh Haxly Raul wrote very warm memories full of both scientific and personal impressions [ 2 ].

In 1983, Padron returned to his homeland and began working at the Venezuelan Institute of Scientific Research, in which he founded and headed the Center for structural biology. In 1997–2011, he was a foreign scholarship holder of the Haward Hughes Medical Institute. The economic and political crisis in Venezuela, especially aggravated after Nicholas Maduro in 2013, turned the work of Padron and his group into a daily feat. In 2017, they stopped paying a salary, from time to time the government turned off the Internet; Communication with foreign colleagues and maintaining the work of the laboratory required incredible efforts. Public transport did not work in the country, there were not enough essential items. Venezuela left 14% of residents, including all four children of the Padron family. Despite this, Raul remained in Karakas, continued his scientific work and regularly published new articles. Only last year, Padron with his wife, also a researcher, moved to the USA and now works at Massachusetts University.

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Many years ago, Raul Padron discovered that microscopic threads formed by motor protein myosin in the muscles of the tarantula is longer and thicker, and, most importantly, are much better ordered than in the muscles of the vertebrates. This makes the tarantula muscles an ideal object for structural research. All muscles are reduced as a result of the interaction of myosin molecules with actin.

The source of energy for mechanical work is the hydrolysis of ATP, catalyzed by myosin, as found in 1938 by V. A. Engelhardt and M. N. Lyubimov. Long core parts of the myosin molecules form the trunks of thick threads, from which globular motor fragments of molecules - heads. When reduced, the muscles of the head are attached to the thin threads formed by other protein - actin, and pull them, which leads to a relative movement of thick and thin threads and a contraction of muscle, the efficiency of which may exceed 50%.

The interaction of a myosine with the assets during muscle contraction increases the speed of ATP hydrolysis by myosin by 1000 times. In the relaxed muscle, the ATP hydrolysis rate is 10 times less than that of isolated myosin heads. Padron and his colleagues determined the structure of the tarantula myosin threads using cryoelectronic microscopy and found that myosin heads fit tightly to the myosin thread trunk and each other, blocking the interaction with the asset and ATP hydrolysis [ 3 ]. This structure with higher resolution is shown in the figure at the right; On the left below is a newborn tarantula.

Later, such structures were found in skeletal and heart muscles of vertebrates. It turned out that dense packaging of the heads on the surface of myosin threads plays a significant role in maintaining a relaxed state of muscle. Moreover, it turned out that in patients with hypertrophic cardiomyopathy, this well -ordered structure is destabilized. Thus, it became clear that to launch muscle contraction it is not enough to open a step to join myosin heads - it is necessary to disassemble the ordered structure on the surface of the myosin thread so that the myosin heads are freed from the neighbors, they can find Aktin monomers and join them. This task in different muscles, apparently, is solved in different ways.

In 2019, Raul, his colleagues from Venezuela and the United States conducted experiments on the APS synchrone in Chicago and received radiological diagrams of the living muscles of the tarantula’s foot at rest (at the center of the figure) and with reduction in various modes. They, in particular, were interested in the role of myosin phosphorylation in the launch of the reduction. It is this work recently published in PNAS .

Our modest contribution was to show that the nuclear model obtained according to cryoelectronic microscopy data perfectly describes the radiopractive picture of the living muscles of the tarantula. Thus, an answer was received to the “damned question” of structural biology: how much the form of biological objects changes in the process of freezing or crystallization when using methods of cryoelectronic microscopy or x -ray crystallography.

It turned out that the structures of the threads and heads of myosin in the muscle of the Tarantula In Vivo muscle are the same as in EM-figures, with accuracy to the resolution of the methods. We also quantitatively estimated the share of myosin heads extending from the barrel of the thread and the muscles involved in various conditions, and the influence of myosin phosphorization on structural changes in the muscles with its reduction.

Even against the background of the raging pandemia Covid-19 heart disease remain the most common cause of death in the world. The study of molecular details of work and muscle regulation can help understand the molecular mechanisms of some heart diseases and contribute to the development of new pharmacological drugs and treatment methods.

Natalia Kubasova, Andrey Tsaturyan (Research Institute of Mechanics of Moscow State University)