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.

FAM46C 是一种非经典的 poly(A) 聚合酶，在多发性骨髓瘤中经常发生突变。FAM46C 功能的丧失促进多发性骨髓瘤的细胞存活，表明其具有肿瘤抑制作用。FAM46C 也是紧固精子头部和鞭毛必不可少的，对男性生育能力必不可少。FAM46C 的这些功能的分子机制仍然难以捉摸。我们报告了 FAM46C 的晶体结构，为其 poly(A) 聚合酶活性提供基础，并使与多发性骨髓瘤相关的突变合理化。此外，我们发现 FAM46C 直接与丝氨酸/苏氨酸激酶 Plk4（中心体复制的主要调节因子）相互作用。我们展示了与 Plk4 的 Cryptic Polo-Box 1-2 域复杂的 FAM46C 的结构。我们基于结构的突变分析表明，与 Plk4 的相互作用将 FAM46C 募集到中心体。我们的数据表明 Plk4 介导的 FAM46C 定位使其能够调节中心体结构和功能，这可能是 FAM46C 在细胞增殖和精子发育中的作用的基础。