A team led by UT Southwestern Medical Center Researchers discovered the atomic structure of a pivot protein complex with the function of mobile eyelashes, hair structures extending from the surfaces of many types of cells that generate their movement.
The results of the researchers involving a radial radius 3 (RS3), reported in Structural and molecular biology of natureHelping to answer certain fundamental questions about the operation of mobile eyelashes and could possibly lead to new treatments for ciliopathies, diseases in which the structure and / or the function of the eyelashes are altered. These include primary ciliary dyskinesia, a genetic disorder that shortens life that causes infertility, chronic respiratory problems, inverted organ placement and excess cerebral fluid.
“Our results reveal RS3 as a unique center connecting mechanical support with energy production and recycling in these highly preserved and movement generators. »»
Daniela Nicastro, PHD, professor, cell biology, UT Southwestern
Dr. Nicastro co-directed the study with Xuewu Zhang, Ph.D., professor of pharmacology and biophysics, and first author Yanhe Zhao, Ph.D., scientific researcher at Nicastro Lab.
The eyelashes are omnipresent on cells, playing a variety of roles, said Dr. Nicastro. While non -mobile eyelashes serve as sensors for chemical and mechanical signals, mobile eyelashes are rhythmicly beat to propel certain types of cells by liquid or to move small objects and liquid in their environment and through tissues.
Scientists have long since known that the oscillatory beat of a mobile eyelash is generated by thousands of molecular motor proteins called dyneines. But the way the cells coordinate their actions to whisk the eyelashes in both directions and from which the energy that comes from this movement is not clear.
To help answer these questions, UTSW researchers and elsewhere have studied the structures of various protein complexes that make up the internal functioning of mobile eyelashes. Most of these studies have used model organizations, such as single cell algae Chlamydomonaswhich move through their aquatic habitats with two mobile eyelashes.
Three of these ciliary complexes make up structures called radial rays, which are repeated several times on the length of the eyelashes and connect the peripheral microtubule cylinder which keeps dyneine motors to a central spine, so that in the cross section, the radial rays resemble the rays of a wheel. While the structures of Chlamydomonas“The radial complexes of speech 1 and 2 (RS1 and RS2) reflect those found in mammals, including humans, Algal RS3 is much shorter than the mammal complex.
Studies of Nicastro Lab have shown that patients carrying mutations that affect RS1 and RS2 but who leave RS3 intacts have less severe ciliopathies than those where the RS3 is also affected, which suggests that RS3 is particularly important for the function of eyelashes. However, the molecular structure of RS3 had been unknown.
To resolve the RS3 structure of mammals, DRS. Nicastro, Zhang and Zhao and their colleagues used a variety of approaches to study RS3 mouse, including high-tech imagery from cryo-electron microscopy (cryo-EM) and cryo-electron tomography as well as proteomics and computer biology.
Their investigation revealed that the mammals’ RS3 is made up of 14 proteins, including 10 previously unknown to be part of this complex. By matching these proteins to those of a complete mouse protein database, the researchers identified them and their functions.
Dr. Zhao said many of RS3 proteins are involved in the placement or elimination of phosphate groups from other proteins – a regulation function that he and his colleagues suspect a role in coordinating the activity of Dynein engines. Several other proteins of this complex are involved in the generation of ATP, a fuel that cells use for energy and which leads to the movement of dyneine.
Together, he said, these results suggest that RS3 components are essential both to synchronize the activity of dyneine and fuel the movement of motors in the eyelashes.
RS3’s structure could act as a plan for the design of drugs that modify its activity, said Dr. Zhang. Such therapies could possibly be used to treat ciliopathies such as polycystic kidney disease and primary eyelash dyskinesia. Researchers plan to continue to study the roles and individual interactions of the proteins that make up RS3 and how this structure could differ between species.
Dr. Nicastro played a central role in creating the UTSW Cryo-EM installation, which she directed until December 2019. The DRE Zhang is a Virginia Murcenthic Stock Exchange in medical research.
