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Structural and Functional Analyses of the FAM46C/Plk4 Complex

Hua Chen1, Defen Lu1, Guijun Shang1

  • 1Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Structure (London, England : 1993)
|May 21, 2020
PubMed

Insights

The study reveals the crystal structure of FAM46C, a poly(A) polymerase linked to multiple myeloma and male fertility. This structure explains its function and interaction with Plk4, crucial for centrosome regulation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • FAM46C, a non-canonical poly(A) polymerase, is frequently mutated in multiple myeloma, where its loss of function promotes cancer cell survival, indicating a tumor-suppressive role.
  • FAM46C is also critical for male fertility, essential for sperm head and flagellum attachment, though its precise molecular functions remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying FAM46C's functions in multiple myeloma and male fertility.
  • To determine the crystal structure of FAM46C to understand its poly(A) polymerase activity and the basis of associated multiple myeloma mutations.
  • To investigate the interaction between FAM46C and Plk4, a key regulator of centrosome duplication.

Main Methods:

  • X-ray crystallography was used to determine the structure of FAM46C and its complex with Plk4.
  • Structure-based mutational analyses were performed to investigate the interaction between FAM46C and Plk4.
  • Biochemical assays were employed to assess poly(A) polymerase activity.

Main Results:

  • The crystal structure of FAM46C was determined, providing insights into its poly(A) polymerase activity and mutations linked to multiple myeloma.
  • FAM46C was found to interact directly with the serine/threonine kinase Plk4, the master regulator of centrosome duplication.
  • Structure-based analyses revealed that the interaction with Plk4 recruits FAM46C to centrosomes, suggesting a role in regulating centrosome structure and function.

Conclusions:

  • The structural and biochemical data provide a mechanistic basis for FAM46C's poly(A) polymerase activity and its link to multiple myeloma.
  • FAM46C's interaction with Plk4 and recruitment to centrosomes suggest a novel role in regulating centrosome duplication and function.
  • These findings offer a molecular understanding of FAM46C's involvement in cell proliferation, cancer, and male fertility, opening avenues for therapeutic strategies.
Keywords:
FAM46CPlk4centrosomekinasepoly(A)structure

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