Actin Filaments: Revealing the Mysteries
Actin filaments are protein structures essential for animal movement and critical for the structural support and shape of cells. Actin filaments are fundamental to various cellular activities such as cell-to-cell contact, DNA organization, muscle contraction, and the cytoskeleton system. Polarization of actin filaments is a well-known phenomenon where one end is growing, known as the barbed end, and one end is shrinking, known as the pointed end. The ends of the filament also interact differently with other proteins in the cell, but the mechanism behind these differences was not clear to scientists. However, recent research at the University of Pennsylvania Perelman School of Medicine used cryo-electron microscopy (cryo-EM) to examine the atomic structures of actin filament ends to reveal missing atomic details of the barbed end and pointed end. With this groundbreaking research, scientists can fill in the details behind many muscular, skeletal, cardiac, neurological, and immunological disorders.
Actin Filament Dynamics: Crucial to Cellular Activities
Actin is the most abundant protein in the cells of higher organisms such as animals. Actin filaments provide key structural support to the cell by serving as building blocks for long, thin structures called filaments. When the actin filament dynamics undergo fast changes, the cell can undergo numerous cellular events, such as movement along surfaces, cell-to-cell contact, and cell division. Actin filaments are also crucial building blocks of muscle fibers, therefore essential for muscle contraction.
The Mechanism Behind the Filamentous Treadmill
Actin filament dynamics are primarily governed by treadmilling, where individual actin proteins detach from the pointed end, and additional barbed ends aggregate to the other end. Proteins that bind to filaments at the end prevent the addition or loss of individual actin proteins, and many other proteins bind to the barbed and pointed ends. The structural details of the actin filament ends, therefore, determine the specificity of these interactions. The structural details and molecular mechanisms that explain why these two ends work so differently are poorly understood. Roberto Dominguez, PhD, William Maul Measey Presidential Professor of Physiology at Penn, says that the results of their study provide a mechanistic understanding of the filamentous treadmill, which affects how we view the cellular roles of actin in health and disease.
Understanding Actin Biology
The research, including two Penn students, Peter Carman, PhD, a recent graduate student in Dominguez’s lab and Kyle Barrie, PhD, a graduate student currently in the lab, analyzes actin filaments to shed light on the ends of the filaments rather than middle. The researchers identified hundreds of thousands of filament end views, allowing them to obtain near-atomic-scale reconstructions. They discovered that the barbed end has a “flat,” uncapped actin shape, while the pointed end has a “twisted,” uncapped actin shape. The data also showed the structural changes induced by two proteins, CapZ at the barbed end and tropomodulin at the pointed end, which cap off actin filaments. These are the proteins found at the ends of the filament in skeletal and cardiac muscles and play an essential role in stabilizing actin filaments in muscle fibers. According to the researchers, without these proteins, our muscles would fall apart.
Insight into Treating Disorders
The results of this study provide crucial mechanistic details for a deeper understanding of actin biology as a whole. This study’s insights will be useful for treating disorders caused by actin dysfunction, as it offers insights into the relationship between actin and diseases affecting the muscular, skeletal, cardiac, neurological, and immunological systems.
Additional Piece
For decades, the inability to understand the mechanistic details of actin filament ends has hindered researchers’ ability to link actin with various diseases. However, the recent research by the University of Pennsylvania’s Perelman School of Medicine uses cryo-EM technology to reveal critical missing atomic details of the barbed end and pointed end of the actin filaments. This research paves the way for further exploration of actin biology, essential because the polarization of actin filaments provides crucial support to animal cells.
Muscular, skeletal, immunological, and neurological diseases result from mutations or dysfunctional actin filaments, and the actin structure is a critical component of many drugs used to treat cancer, heart disease, and autoimmune disorders. Studies have shown that chronic autoimmune diseases such as rheumatoid arthritis and lupus affect the actin structure of patients’ cells and that manipulation of actin’s structure may improve or even cure these diseases.
Most drugs that manipulate actin dynamics target downstream regulators, such as the Rho-family small GTPases, which have led to successes and failures in clinical trials. However, these drugs’ reliability is hampered by off-target effects, toxicities, and lack of efficacy. Understanding actin’s mechanistic details will enable researchers to create more targeted drugs while minimizing off-target effects and toxicities.
In conclusion, understanding the structural and molecular mechanism of actin filaments, particularly at the ends of the filament, will benefit modern science, medicine, and technology, making it crucial to accelerate research in this area. Only then can we achieve transformational improvements in the prevention and treatment of various diseases caused by actin dysfunctions or deficiencies.
Summary:
Actin filaments, protein structures, have an inherent polarity with their physical characteristics. They are fundamental for animal movement and provide crucial structural support to the cells, which includes various cellular events such as muscle contraction, cytoskeleton, cell division, and cell-to-cell contact. However, scientists were not clear about the mechanism that determines these differences. Recent research by the University of Pennsylvania’s Perelman School of Medicine reveals key atomic structures of the ends of the actin filament using a technique called cryo-electron microscopy (cryo-EM). This study provides fundamental information that helps fill details for muscular, skeletal, cardiac, immunological, and neurological disorders caused by actin defects or deficiencies. The study sheds light on the mechanisms behind filamentous treadmills and allows for the understanding of processes that have been known for decades.
The summary of the article is embedded in the additional piece.
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Actin filaments, protein structures critical for living movement from individual cells to animals, have long been known to have polarity associated with their physical characteristics, with growing “barbed” and shrinking “spiky” ends. The ends of the filament are also different in the way that they interact with other proteins in cells. However, the mechanism that determines these differences has never been entirely clear to scientists. Now, researchers at the University of Pennsylvania Perelman School of Medicine have revealed key atomic structures of the ends of the actin filament using a technique called cryo-electron microscopy (cryo-EM). The study, published in Scienceprovides fundamental information that can help fill in the details behind disorders affecting some muscular, skeletal, cardiac, neurological, and immunological disorders that are the result of actin defects or deficiencies.
Actin is the most abundant protein within the cells of higher organisms, such as animals. It serves as the building block for long, thin structures called filaments, which provide key structural support as part of the cell’s “cytoskeleton,” the system that gives cells their shape and polarity. Rapid changes in actin filaments underlie key cellular events, such as movement along surfaces, cell-to-cell contact, and cell division. Actin filaments are also important building blocks in muscle fibers.
“The results of our study provide a mechanistic understanding of a process we have known about for more than 40 years, known as the filamentous treadmill, and it affects how we view the cellular roles of actin in health and disease.” said the study’s lead author. Roberto Dominguez, PhD, William Maul Measey Presidential Professor of Physiology at Penn.
Actin filament dynamics is largely governed by the process of “treadmilling,” through which individual actin proteins are detached from one end of the filament, known as the pointy end, and aggregated to the other end with barbed Actin filaments can be stabilized by various so-called “guard” proteins that bind to the ends of the filaments to stop the further addition or loss of individual actin proteins. Many other proteins also bind to the barbed and pointed ends of the actin filament. But the structural details that determine the specificity of these interactions, the details that explain why these two extremes work so differently, have been hazy.
In their study, the researchers, including two Penn students (Peter Carman, PhD, a recent graduate student in Dominguez’s lab, and Kyle Barrie, PhD, a graduate student currently in the lab, who served as co-first author), analyzed actin filaments by cryo-EM. With this high-resolution imaging technique, a researcher takes many thousands of snapshots of a target molecule, computationally aligns them, and then averages them to reduce random “noise” in the image, producing a three-dimensional reconstruction of the molecule that can be sharp enough to visualize individual atoms.
With the help of artificial intelligence (AI), the researchers were able to focus on the ends of the filaments rather than the middle, as had been the norm in similar research before. In doing so, they identified hundreds of thousands of filament end views, enabling them to obtain near-atomic-scale reconstructions. These revealed a “flat” actin shape or conformation at the barbed end without a cap, versus a “twisted” conformation at the pointed end without a cap.
The data also detailed the structural changes induced by two proteins that cap off actin filaments, CapZ at the barbed end and tropomodulin at the pointed end. These are the two proteins found at the ends of the filament in skeletal and cardiac muscles, playing an essential role in stabilizing actin filaments in muscle fibers, and without these proteins our muscles would fall apart.
The results of this study provide crucial mechanistic details for a deeper understanding of actin biology as a whole. The researchers believe that insights from this study should also be useful in understanding and ultimately treating disorders caused by actin dysfunction.
Funding was provided by the National Institutes of Health (R01 GM073791, F31 HL156431).
https://www.sciencedaily.com/releases/2023/06/230608120933.htm
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