Researchers at the University of Pennsylvania School of Medicine have discovered that a protein called leiomodin (Lmod) promotes the assembly of an important heart muscle protein called actin. What’s more, Lmod directs the assembly of actin to form the pumping unit of the heart. The findings appear in this week’s issue of Science.
“Very little was known about Lmod when we began this study,” says lead author Roberto Dominguez, PhD, Associate Professor of Physiology.
“It appeared that this protein was present in muscle cells but this had not been demonstrated directly and nobody knew what it did,” explains Dominguez. “We compared the amino acid sequence of Lmod with the sequence of another protein called tropomodulin [Tmod] that was already known to bind actin filaments in muscle cells. We found that one part of Lmod was very similar to Tmod, but Lmod was a bigger protein than Tmod and contained unique features that made us suspect that it could assemble the actin filaments of the heart muscle. This is exactly what we found.”
The results answer a question that scientists studying the heart have long asked: What controls the assembly of the pumping unit of the heart?
Actin is the most abundant protein in most animal cells and forms long polymers, or filaments, that make up the cell skeleton. In the cells that make up muscles and the heart, interactions of actin filaments with motor proteins produce the contractions that pump blood through the body.
Actin spontaneously forms polymers in test tubes, but living cells use nucleator proteins to control the time and place where actin filaments forms. “For a long time, physiologists have wondered what serves as the nucleator protein in cardiac muscle cells,” says co-author Professor Thomas Pollard, PhD, of Yale University. “It was very satisfying after all these years to discover that Lmod can serve as the nucleator protein to initiate the forming of actin polymers in heart muscle cells.”
Lmod also directs actin filaments to the sarcomere, the part of the heart that controls contractions or pumping. When Lmod was knocked down in cardiac muscle cells by an RNA silencing technique, the sarcomeres became completely disorganized and could not direct muscles to contract.
Proper localization of Lmod in heart cells is critical, because even moderately elevated levels promote the formation of abnormal actin bundles in the nuclei of cardiac muscle cells where actin does not belong. A similar disorganization of actin bundles is characteristic of a disease of skeletal muscle weakness called intranuclear rod myopathy. Although this disease is caused by a mutation in a skeletal muscle-specific actin gene, the similarity in appearance suggests that mutations in Lmod could cause the same type of disease in cardiac muscle cells.
The Penn team is currently studying how the heart regulates the level of Lmod and how Lmod might be relevant to cardiac muscle disease. In addition, the team is attempting to crystallize Lmod in order to study its structure directly.
Malgorzata Boczkowska of Penn and David Chereau of Boston Biomedical Institute are co-first authors of this study. Other key contributors are Pekka Lappalainen and Aneta Skwarbek-Maruszewska of the University of Helsinki; Ikuko Fujiwara of Yale; David B. Hayes of Boston Biomedical Institute; and Grzegorz Rebowski of Penn. The study was supported by grants from the National Heart Lung and Blood Institute and the National Institute of General Medical Sciences.
PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #3 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals — its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center — a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
Karen Kreeger | EurekAlert!
The balancing act: An enzyme that links endocytosis to membrane recycling
07.12.2016 | National Centre for Biological Sciences
Transforming plant cells from generalists to specialists
07.12.2016 | Duke University
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
07.12.2016 | Health and Medicine
07.12.2016 | Life Sciences
07.12.2016 | Health and Medicine