@article{2c4fb428f21448cebd0f7441c4973f00,
title = "Structural and Functional Analyses of the FAM46C/Plk4 Complex",
abstract = "FAM46C, a non-canonical poly(A) polymerase, is frequently mutated in multiple myeloma. Loss of function of FAM46C promotes cell survival of multiple myeloma, suggesting a tumor-suppressive role. FAM46C is also essential for fastening sperm head and flagellum, indispensable for male fertility. The molecular mechanisms of these functions of FAM46C remain elusive. We report the crystal structure of FAM46C to provide the basis for its poly(A) polymerase activity and rationalize mutations associated with multiple myeloma. In addition, we found that FAM46C interacts directly with the serine/threonine kinase Plk4, the master regulator of centrosome duplication. We present the structure of FAM46C in complex with the Cryptic Polo-Box 1-2 domains of Plk4. Our structure-based mutational analyses show that the interaction with Plk4 recruits FAM46C to centrosomes. Our data suggest that Plk4-mediated localization of FAM46C enables its regulation of centrosome structure and functions, which may underlie the roles for FAM46C in cell proliferation and sperm development.",
keywords = "FAM46C, Plk4, centrosome, kinase, poly(A), structure",
author = "Hua Chen and Defen Lu and Guijun Shang and Guoming Gao and Xuewu Zhang",
note = "Funding Information: We thank Hongtao Yu, Benjamin Weaver and Yi Weaver for discussions and microscope usage, and the structural biology laboratory at University of Southwestern Medical Center (UTSW) for assistance on crystallization and data collection. This work is supported in part by grants from the National Institutes of Health ( 1R01CA220283 and P50CA196516 ) and the Welch Foundation ( I-1702 ) to X.Z. X.Z. is a Virginia Murchison Linthicum Scholar in Medical Research at UTSW. Results shown in this report are derived from work performed at the Argonne National Laboratory, Structural Biology Center at the Advance Photon Source. Argonne is operated by University of Chicago, Argonne for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Funding Information: We thank Hongtao Yu, Benjamin Weaver and Yi Weaver for discussions and microscope usage, and the structural biology laboratory at University of Southwestern Medical Center (UTSW) for assistance on crystallization and data collection. This work is supported in part by grants from the National Institutes of Health (1R01CA220283 and P50CA196516) and the Welch Foundation (I-1702) to X.Z. X.Z. is a Virginia Murchison Linthicum Scholar in Medical Research at UTSW. Results shown in this report are derived from work performed at the Argonne National Laboratory, Structural Biology Center at the Advance Photon Source. Argonne is operated by University of Chicago, Argonne for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. G.S. H.C. and X.Z. conceived the project. G.S. H.C. G.G. and X.Z. determined the crystal structures. H.C. G.S. and G.G. carried out the biochemical analyses. D.L. and H.C. performed the cell-based experiments. H.C. D.L. G.S. and X.Z. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd",
year = "2020",
month = aug,
day = "4",
doi = "10.1016/j.str.2020.04.023",
language = "English (US)",
volume = "28",
pages = "910--921.e4",
journal = "Structure",
issn = "0969-2126",
publisher = "Cell Press",
number = "8",
}