Structural and Functional Analyses of the FAM46C/Plk4 Complex

Chen, Hua; Lu, Defen; Shang, Guijun; Gao, Guoming; Zhang, Xuewu

doi:10.1016/j.str.2020.04.023

Cited by 8 publications

(22 citation statements)

References 66 publications

(83 reference statements)

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“…In terms of conformational difference, FAM46B as well as prokaryotic PAPs and CCAs possess an inter‐domain salt bridge that involves one of the consensus catalytic residues, but mmFAM46C lacks it (Figure 3B ). However, this salt bridge remains intact in the recently reported hsFAM46C structure (Supplementary Figure S8 ) [ 58 ]. While human and mouse FAM46C showed similar PAP activity [ 38 ], it seems that such local conformational variation in the ligand‐free state does not account for PAP efficiency.…”

Section: Discussionmentioning

confidence: 96%

Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C

Zhang

et al. 2021

Cancer Communications

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Background: Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of aberrant plasma cells within the bone marrow.The high frequent mutation of family with sequence similarity 46, member C (FAM46C) is closely related with the occurrence and progression of MM.Recently, FAM46C has been identified as a non-canonical poly(A) polymerase (PAP) that functions as a tumor suppressor in MM. This study aimed to elucidate the structural features of this novel non-canonical PAP and how MM-related mutations affect the structural and biochemical properties of FAM46C, eventually advancing our understandings towards FAM46C mutation-related MM occurrence. Methods: We purified and crystallized a mammalian FAM46C construct, and solved its structure. Next, we characterized the property of FAM46C as a PAP through a combination of structural analysis, site-directed mutagenesis and biochemical assays, and by comparison with its homolog FAM46B. Finally, we structurally analyzed MM-related FAM46C mutations and tested the enzymatic activity of corresponding mutants. Results: We determined the crystal structure of a mammalian FAM46C protein at 2.35 Å, and confirmed that FAM46C preferentially consumed adenosine triphosphate (ATP) and extended A-rich RNA substrates. FAM46C showed a weaker PAP activity than its homolog FAM46B, and this difference was largely dependent on the residue variance at particular sites. Of them, residues at positions 77, 290, and 298 of mouse FAM46C were most important for the divergence in enzymatic activity. Among the MM-associated FAM46C mutants, those residing at the catalytic site (D90G and D90H) or putative RNA-binding site (I155L, S156F, D182Y, F184L, Y247V, and M270V) showed abolished or compromised PAP activity of FAM46C, while N72A and S248A did not severely affect the PAP activity. FAM46C mutants D90G, D90H, I155L, S156F, F184L, Y247V, and M270V hadThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Section: Discussionmentioning

confidence: 96%

Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C

Zhang

et al. 2021

Cancer Communications

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“…Independent groups showed that FAM46C polyadenylates Ig and endoplasmic reticulum (ER)-targeted mRNAs, sustains antibody responses in vitro and in vivo, and activates the unfolded protein response (UPR), suggesting a possible link with proteostasis in the secretory compartment (Bilska et al, 2020;Herrero et al, 2020;Mroczek et al, 2017). Moreover, the structure of FAM46C and its nucleotidyl-transferase catalytic site has recently been described (Chen et al, 2020). However, how FAM46C selectively harnesses the expression of ER-targeted proteins and how this function is regulated are unresolved issues.…”

Section: Introductionmentioning

confidence: 99%

The Interaction of the Tumor Suppressor FAM46C with p62 and FNDC3 Proteins Integrates Protein and Secretory Homeostasis

Fucci¹,

Resnati²,

Riva³

et al. 2020

Cell Reports

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“…Moreover, an additional cellular role has been recently identified that may contribute to explain the unique oncosuppressive role of FAM46C. It appeared to directly interact with the Polo‐Box 1‐2 domains of Polo‐like Kinase 4 (PLK4), the master regulator of centrosome duplication [127,130]. This interaction was shown to not require or affect FAM46C poly(A)polymerase activity or PLK4 binding with other centrosomal proteins (Cep192 and Cep152) [127].…”

Section: X‐box Binding Protein 1 (Xbp1)mentioning

confidence: 99%

“…It appeared to directly interact with the Polo‐Box 1‐2 domains of Polo‐like Kinase 4 (PLK4), the master regulator of centrosome duplication [127,130]. This interaction was shown to not require or affect FAM46C poly(A)polymerase activity or PLK4 binding with other centrosomal proteins (Cep192 and Cep152) [127]. Through this interaction, FAM46C is recruited to the centrosome where it inhibits PLK4 autophosphorylation, cell growth and invasiveness in different cancer models [127,130].…”

Section: X‐box Binding Protein 1 (Xbp1)mentioning

confidence: 99%

“…This interaction was shown to not require or affect FAM46C poly(A)polymerase activity or PLK4 binding with other centrosomal proteins (Cep192 and Cep152) [127]. Through this interaction, FAM46C is recruited to the centrosome where it inhibits PLK4 autophosphorylation, cell growth and invasiveness in different cancer models [127,130]. Even though the capacity of FAM46C to block centrosome duplication is still debated, expression of a mutated version of FAM46C unable to bind PLK4 but likely maintaining the poly(A)polymerase activity lacks the oncosuppressive effects, suggesting a mechanistic role of this interaction in the tumor suppressive activity [127].…”

Section: X‐box Binding Protein 1 (Xbp1)mentioning

confidence: 99%

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The Immunity‐malignancy equilibrium in multiple myeloma: lessons from oncogenic events in plasma cells

2021

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Structural and Functional Analyses of the FAM46C/Plk4 Complex

Cited by 8 publications

References 66 publications

Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C

Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C

The Interaction of the Tumor Suppressor FAM46C with p62 and FNDC3 Proteins Integrates Protein and Secretory Homeostasis

The Immunity‐malignancy equilibrium in multiple myeloma: lessons from oncogenic events in plasma cells

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