TY - JOUR
T1 - Human IFT-A complex structures provide molecular insights into ciliary transport
AU - Jiang, Meiqin
AU - Palicharla, Vivek Reddy
AU - Miller, Darcie
AU - Hwang, Sun Hee
AU - Zhu, Hanwen
AU - Hixson, Patricia
AU - Mukhopadhyay, Saikat
AU - Sun, Ji
N1 - Funding Information:
We thank the Cryo-electron Microscopy Center at St. Jude Children’s Research Hospital for help with cryo-EM data collection, Kevin White and the Quantitative Light Microscopy Core Facility in UT Southwestern for imaging, members of the Sun lab for helpful discussions and Ines Chen for manuscript revision. This work was funded by the American Lebanese Syrian Associated Charities (ALSAC), NIH (R00HL143037 to J.S., R35GM144136 to S.M., and 1S10OD028630 to the Microscopy Core Facility in UT Southwestern). We acknowledge the kind gifts of reagents from Greg Pazour and Tamara Caspary.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/4
Y1 - 2023/4
N2 - Intraflagellar transport (IFT) complexes, IFT-A and IFT-B, form bidirectional trains that move along the axonemal microtubules and are essential for assembling and maintaining cilia. Mutations in IFT subunits lead to numerous ciliopathies involving multiple tissues. However, how IFT complexes assemble and mediate cargo transport lacks mechanistic understanding due to missing high-resolution structural information of the holo-complexes. Here we report cryo-EM structures of human IFT-A complexes in the presence and absence of TULP3 at overall resolutions of 3.0–3.9 Å. IFT-A adopts a “lariat” shape with interconnected core and peripheral subunits linked by structurally vital zinc-binding domains. TULP3, the cargo adapter, interacts with IFT-A through its N-terminal region, and interface mutations disrupt cargo transport. We also determine the molecular impacts of disease mutations on complex formation and ciliary transport. Our work reveals IFT-A architecture, sheds light on ciliary transport and IFT train formation, and enables the rationalization of disease mutations in ciliopathies.
AB - Intraflagellar transport (IFT) complexes, IFT-A and IFT-B, form bidirectional trains that move along the axonemal microtubules and are essential for assembling and maintaining cilia. Mutations in IFT subunits lead to numerous ciliopathies involving multiple tissues. However, how IFT complexes assemble and mediate cargo transport lacks mechanistic understanding due to missing high-resolution structural information of the holo-complexes. Here we report cryo-EM structures of human IFT-A complexes in the presence and absence of TULP3 at overall resolutions of 3.0–3.9 Å. IFT-A adopts a “lariat” shape with interconnected core and peripheral subunits linked by structurally vital zinc-binding domains. TULP3, the cargo adapter, interacts with IFT-A through its N-terminal region, and interface mutations disrupt cargo transport. We also determine the molecular impacts of disease mutations on complex formation and ciliary transport. Our work reveals IFT-A architecture, sheds light on ciliary transport and IFT train formation, and enables the rationalization of disease mutations in ciliopathies.
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U2 - 10.1038/s41422-023-00778-3
DO - 10.1038/s41422-023-00778-3
M3 - Article
C2 - 36775821
AN - SCOPUS:85147896460
SN - 1001-0602
VL - 33
SP - 288
EP - 298
JO - Cell Research
JF - Cell Research
IS - 4
ER -