A team led by scientists at Van Andel Research Institute (VARI) has revealed for the first time the atomic-level structure of a promising drug target for conditions such as stroke and traumatic brain injury.
Called TRPM4, this protein is found in tissues throughout the body, including the brain, heart, kidney, colon and intestines, where it plays a major role in regulating blood flow via blood vessel constriction as well as setting the heart's rhythm and moderating immune responses.
"Understanding the role TRPM4 plays in regulating circulation is vital, but for years research has been limited by a lack of insight about its molecular architecture," said Wei Lü, Ph.D., an assistant professor at VARI and lead author on a study describing TRPM4's structure, published today in Nature. "Our findings not only provide a detailed, atomic-level map of this critical protein, but also reveal completely unexpected facets of its makeup."
TRPM4 is critically involved in regulating the blood supply to the brain, which comprises only about 2 percent of the body's total weight yet receives 15 to 20 percent of its blood supply. Conditions that disrupt blood flow in the brain, such as stroke, traumatic brain injury, cerebral edema and hypertension, can have devastating consequences and are significant public health problems.
"Many safeguards exist in the brain's circulatory system to protect against a sudden interruption in blood supply, one of which is TRPM4," Lü said. "We hope that a better understanding of what this protein looks like will give scientists a molecular blueprint on which to base the design of more effective medications with fewer side effects."
The structure of TRPM4 is markedly different from the other molecules in the TRP superfamily, a category of proteins that mediate responses to sensations and sensory stimuli, such as pain, pressure, vision, temperature and taste. Broadly known as ion channels, proteins like TRP nestle within cells' membranes, acting as gatekeepers for chemical signals passing into and out of the cell.
Even within its own subfamily, which comprises eight molecules in total, TRPM4 appears to be wholly unique. Today's publication represents the first atomic view of a member of the TRPM subfamily.
It reveals a crown-like structure, with the four peaks composing a large N-terminal domain--a hallmark of TRPM proteins. This region, found at the start of the molecule, is a major site of interaction with the cellular environment and other molecules in the body. On the opposite end of TRPM4, commonly called the C-terminal domain, Lü's team found an umbrella-like structure supported by a "pole" and four helical "ribs"--characteristics that have never before been observed.
The findings were made possible by VARI's state-of-the-art David Van Andel Advanced Cryo-Electron Microscopy Suite, which allows scientists to view some of life's smallest components in exquisite detail. VARI's largest microscope, the Titan Krios, is one of fewer than 120 in the world and is so powerful that it can visualize molecules 1/10,000th the width of a human hair.
In addition to Lü, VARI Assistant Professor Juan Du, Ph.D., also is an author on today's paper. Paige A. Winkler, Ph.D., and Yihe Huang, Ph.D., both postdoctoral fellows in Lü's lab, and Weinan Sun, Ph.D., a postdoctoral associate in the Spruston Lab at Howard Hughes Medical Institute Janelia Research Campus, are co-first authors.
ABOUT VAN ANDEL RESEARCH INSTITUTE
Van Andel Institute (VAI) is an independent nonprofit biomedical research and science education organization committed to improving the health and enhancing the lives of current and future generations. Established by Jay and Betty Van Andel in 1996 in Grand Rapids, Michigan, VAI has grown into a premier research and educational institution that supports the work of more than 360 scientists, educators and staff. Van Andel Research Institute (VARI), VAI's research division, is dedicated to determining the epigenetic, genetic, molecular and cellular origins of cancer, Parkinson's and other diseases and translating those findings into effective therapies. The Institute's scientists work in onsite laboratories and participate in collaborative partnerships that span the globe. Learn more about Van Andel Institute or donate by visiting http://www.
Beth Hinshaw Hall | EurekAlert!
New eDNA technology used to quickly assess coral reefs
18.04.2019 | University of Hawaii at Manoa
New automated biological-sample analysis systems to accelerate disease detection
18.04.2019 | Polytechnique Montréal
A stellar flare 10 times more powerful than anything seen on our sun has burst from an ultracool star almost the same size as Jupiter
A localization phenomenon boosts the accuracy of solving quantum many-body problems with quantum computers which are otherwise challenging for conventional computers. This brings such digital quantum simulation within reach on quantum devices available today.
Quantum computers promise to solve certain computational problems exponentially faster than any classical machine. “A particularly promising application is the...
The technology could revolutionize how information travels through data centers and artificial intelligence networks
Engineers at the University of California, Berkeley have built a new photonic switch that can control the direction of light passing through optical fibers...
Physicists observe how electron-hole pairs drift apart at ultrafast speed, but still remain strongly bound.
Modern electronics relies on ultrafast charge motion on ever shorter length scales. Physicists from Regensburg and Gothenburg have now succeeded in resolving a...
Engineers create novel optical devices, including a moth eye-inspired omnidirectional microwave antenna
A team of engineers at Tufts University has developed a series of 3D printed metamaterials with unique microwave or optical properties that go beyond what is...
17.04.2019 | Event News
15.04.2019 | Event News
09.04.2019 | Event News
18.04.2019 | Life Sciences
18.04.2019 | Physics and Astronomy
18.04.2019 | Life Sciences