Cilia’s Inner Workings Revealed: Key Protein Structure Unlocked
Potential for New Ciliopathy Treatments Emerges
Researchers at UT Southwestern Medical Center have deciphered the atomic blueprint of a crucial protein complex within motile cilia, the tiny hair-like appendages that drive cell movement. This breakthrough could pave the way for novel therapies targeting debilitating genetic disorders.
Unveiling the Radial Spoke 3 Complex
A multi-disciplinary team, spearheaded by **Daniela Nicastro, Ph.D.**, Professor of Cell Biology, and **Xuewu Zhang, Ph.D.**, Professor of Pharmacology and Biophysics at UT Southwestern, successfully mapped the structure of radial spoke 3 (RS3). This complex plays a vital role in the coordinated beating of cilia.
The findings, published in Nature Structural & Molecular Biology, shed light on the fundamental mechanisms governing cilia function. Understanding these structures is key to addressing ciliopathies, a group of diseases stemming from impaired cilia, such as primary ciliary dyskinesia. This genetic disorder can lead to infertility and severe respiratory issues.
“Our findings reveal RS3 as a unique hub connecting mechanical support with energy production and recycling in these highly conserved, motion-generating organelles.”
—Daniela Nicastro, Ph.D., Professor of Cell Biology
A Deeper Dive into Cilia’s Machinery
Cilia’s rhythmic motion is powered by thousands of dynein motor proteins. However, the precise coordination of these motors and the source of their energy have remained elusive. Previous studies often relied on model organisms like the green alga *Chlamydomonas*.
While the structures of two other radial spoke complexes (RS1 and RS2) are similar between algae and mammals, the algal RS3 differs significantly in length from its mammalian counterpart. Research from the **Nicastro** Lab indicated that RS3’s integrity is paramount, with mutations affecting it leading to more severe ciliopathies.
Mammalian RS3 Structure Mapped
Utilizing advanced techniques including cryo-electron microscopy (cryo-EM), cryo-electron tomography, proteomics, and computational biology, the UTSW team elucidated the mammalian RS3 structure. Their investigation revealed that RS3 is composed of 14 proteins, with 10 previously unrecognized members identified.
“Several of RS3’s proteins are involved in placing or removing phosphate groups from other proteins – a regulatory function that he and his colleagues suspect plays a part in coordinating the activity of the dynein motors,” stated **Yanhe Zhao, Ph.D.**, Research Scientist in the **Nicastro** Lab and lead author. “Several other proteins in this complex are involved in generating ATP, a fuel that cells use for energy and that drives dynein motion.”
The discovered structure of RS3 can serve as a guide for designing drugs aimed at modulating its activity. Such therapeutic interventions could eventually offer new treatment avenues for conditions like polycystic kidney disease and primary ciliary dyskinesia.
The National Institutes of Health and the Cancer Prevention and Research Institute of Texas provided funding for this pivotal research.
