Molecular dance keeps your heart beating

Date:
October 14, 2020
Source:
Washington State University
Summary:
New research demonstrates a molecular dance that keeps your heart
beating. The findings could someday lead to improved diagnostics
and medical treatments for serious and sometimes devastating
hereditary heart conditions.



FULL STORY ==========================================================================
It might look like a little game at the molecular scale.


========================================================================== Filament-like proteins in heart muscle cells have to be exactly the same
length so that they can coordinate perfectly to make the heart beat.

Another protein decides when the filament is the right size and puts a
wee little cap on it. But, if that protein makes a mistake and puts the
cap on too early, another protein, leiomodin, comes along and knocks
the cap out of the way.

This little dance at the molecular scale might sound insignificant,
but it plays a critical role in the development of healthy heart and
other muscles.

Reporting in the journal, Plos Biology, a WSU research team has proven
for the first time how the mechanism works.

The finding could someday lead to improved diagnostics and medical
treatments for serious and sometimes devastating hereditary heart
conditions that come about from genetic mutations in the proteins. One
of these conditions, cardiomyopathy, affects as many as one in 500
people around the world and can often be fatal or have lifetime health consequences. A similar condition called nemaline myopathy affects
skeletal muscles throughout the body with often devastating consequences.

"Mutations in these proteins are found in patients with myopathy," said
Alla Kostyukova, associate professor in the Gene and Linda Voiland School
of Chemical Engineering and Bioengineering and leader of the project. "Our
work is to prove that these mutations cause these problems and to propose strategies for treatment." Heart muscle is made of tiny thick and thin filaments of proteins. With the help of electrical signals, the rope-like filaments bind and unbind in an intricate and precise architecture,
allowing heart muscle to contract and beat.



==========================================================================
The thin filaments are made of actin, the most abundant protein in the
human body. Tropomysin, another protein, wraps itself around the actin filaments.

Tropomyosin together with two other proteins, tropomodulin and leiomodin,
at the end of the actin filaments act as a sort of cap and determine
the filament length.

"It's beautifully designed," said Kostyukova, whose research is focused
on understanding protein structures.

And, tightly regulated.

To keep heart muscle healthy, the actin filaments, which are about a
micron long, all have to be the exact same length. In families with cardiomyopathy, genetic mutations result in formation of filaments that
are either too short or too long. Those affected can have significant
heart problems that cause disability, illness and death.

In a project that spanned seven years, the researchers proved that
leiomodin attaches to the end of the actin filament and kicks out the
other protein, tropomodulin, to assure the actin filament's proper length.



========================================================================== "This is the first time that this has been shown with the atomic-level precision," said Dmitri Tolkatchev, research assistant professor
in the Voiland School and lead author on the paper. "Previously,
several laboratories attempted to solve this problem with very little
success. With our data we finally have a direct proof." The researchers
used state-of-the-art approaches to make the key proteins and study them
at the molecular and cellular level. The work entailed designing the
molecules, constructing them at the gene level in a plasmid, and then
producing them into bacterial or cardiac cells. The researchers used
nuclear magnetic resonance, which works on the same physical principle as Magnetic Resonance Imaging (MRIs), to understand the proteins' binding
at the atomic level. They also used molecular dynamic simulation to
model them.

"The probability of being able to show this mechanism was not high, but
the impact of the discovery is," said Tolkatchev, an expert in nuclear
magnetic resonance. "This was a very important problem to study and
could have a significant impact in the field of muscle mechanics."
The researchers hope to continue the work, identifying additional
components and molecular mechanisms that regulate thin filament
architecture, whether diseased or healthy.


========================================================================== Story Source: Materials provided by Washington_State_University. Original written by Tina Hilding. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Dmitri Tolkatchev, Garry E. Smith, Lauren E. Schultz, Mert Colpan,
Gregory L. Helms, John R. Cort, Carol C. Gregorio, Alla
S. Kostyukova.

Leiomodin creates a leaky cap at the pointed end of actin-thin
filaments.

PLOS Biology, 2020; 18 (9): e3000848 DOI:
10.1371/journal.pbio.3000848 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201014082758.htm

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