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==Crystal structure of the FAM46C/Plk4/Cep192 complex==
==Crystal structure of the FAM46C/Plk4/Cep192 complex==
<StructureSection load='6w3j' size='340' side='right'caption='[[6w3j]]' scene=''>
<StructureSection load='6w3j' size='340' side='right'caption='[[6w3j]], [[Resolution|resolution]] 4.38&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W3J OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W3J FirstGlance]. <br>
<table><tr><td colspan='2'>[[6w3j]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W3J OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W3J FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w3j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w3j OCA], [http://pdbe.org/6w3j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w3j RCSB], [http://www.ebi.ac.uk/pdbsum/6w3j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w3j ProSAT]</span></td></tr>
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TENT5C, FAM46C ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), PLK4, SAK, STK18 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CEP192, KIAA1569, PP8407 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Polynucleotide_adenylyltransferase Polynucleotide adenylyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.19 2.7.7.19] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w3j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w3j OCA], [http://pdbe.org/6w3j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w3j RCSB], [http://www.ebi.ac.uk/pdbsum/6w3j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w3j ProSAT]</span></td></tr>
</table>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/TET5C_HUMAN TET5C_HUMAN]] Nucleotidyltransferase that act as a non-canonical poly(A) RNA polymerase which enhances mRNA stability and gene expression. Mainly targets mRNAs encoding endoplasmic reticulum-targeted protein and may be involved in induction of cell death.<ref>PMID:27060136</ref> <ref>PMID:28931820</ref>  (Microbial infection) Seems to enhance replication of some viruses, including yellow fever virus, in response to type I interferon.<ref>PMID:21478870</ref>  [[http://www.uniprot.org/uniprot/CE192_HUMAN CE192_HUMAN]] Required for mitotic centrosome maturation and bipolar spindle assembly (PubMed:25042804, PubMed:17980596, PubMed:18207742). Appears to be a major regulator of pericentriolar material (PCM) recruitment, centrosome maturation, and centriole duplication (PubMed:25042804, PubMed:17980596, PubMed:18207742). Centrosome-specific activating scaffold for AURKA and PLK1 (PubMed:25042804).<ref>PMID:17980596</ref> <ref>PMID:18207742</ref> <ref>PMID:25042804</ref>  [[http://www.uniprot.org/uniprot/PLK4_HUMAN PLK4_HUMAN]] Serine/threonine-protein kinase that plays a central role in centriole duplication. Able to trigger procentriole formation on the surface of the parental centriole cylinder, leading to the recruitment of centriole biogenesis proteins such as SASS6, CENPJ/CPAP, CCP110, CEP135 and gamma-tubulin. When overexpressed, it is able to induce centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole during S phase. Phosphorylates 'Ser-151' of FBXW5 during the G1/S transition, leading to inhibit FBXW5 ability to ubiquitinate SASS6. Its central role in centriole replication suggests a possible role in tumorigenesis, centrosome aberrations being frequently observed in tumors. Also involved in trophoblast differentiation by phosphorylating HAND1, leading to disrupt the interaction between HAND1 and MDFIC and activate HAND1. Phosphorylates CDC25C and CHEK2.<ref>PMID:16326102</ref> <ref>PMID:16244668</ref> <ref>PMID:17681131</ref> <ref>PMID:18239451</ref> <ref>PMID:19164942</ref> <ref>PMID:21725316</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.
Structural and Functional Analyses of the FAM46C/Plk4 Complex.,Chen H, Lu D, Shang G, Gao G, Zhang X Structure. 2020 May 12. pii: S0969-2126(20)30169-6. doi:, 10.1016/j.str.2020.04.023. PMID:32433990<ref>PMID:32433990</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6w3j" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Chen H]]
[[Category: Polynucleotide adenylyltransferase]]
[[Category: Lu DF]]
[[Category: Chen, H]]
[[Category: Shang GJ]]
[[Category: Lu, D F]]
[[Category: Zhang XW]]
[[Category: Shang, G J]]
[[Category: Zhang, X W]]
[[Category: Rna polymerase]]
[[Category: Transferase]]

Revision as of 09:42, 3 June 2020

Crystal structure of the FAM46C/Plk4/Cep192 complexCrystal structure of the FAM46C/Plk4/Cep192 complex

Structural highlights

6w3j is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:TENT5C, FAM46C (HUMAN), PLK4, SAK, STK18 (HUMAN), CEP192, KIAA1569, PP8407 (HUMAN)
Activity:Polynucleotide adenylyltransferase, with EC number 2.7.7.19
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TET5C_HUMAN] Nucleotidyltransferase that act as a non-canonical poly(A) RNA polymerase which enhances mRNA stability and gene expression. Mainly targets mRNAs encoding endoplasmic reticulum-targeted protein and may be involved in induction of cell death.[1] [2] (Microbial infection) Seems to enhance replication of some viruses, including yellow fever virus, in response to type I interferon.[3] [CE192_HUMAN] Required for mitotic centrosome maturation and bipolar spindle assembly (PubMed:25042804, PubMed:17980596, PubMed:18207742). Appears to be a major regulator of pericentriolar material (PCM) recruitment, centrosome maturation, and centriole duplication (PubMed:25042804, PubMed:17980596, PubMed:18207742). Centrosome-specific activating scaffold for AURKA and PLK1 (PubMed:25042804).[4] [5] [6] [PLK4_HUMAN] Serine/threonine-protein kinase that plays a central role in centriole duplication. Able to trigger procentriole formation on the surface of the parental centriole cylinder, leading to the recruitment of centriole biogenesis proteins such as SASS6, CENPJ/CPAP, CCP110, CEP135 and gamma-tubulin. When overexpressed, it is able to induce centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole during S phase. Phosphorylates 'Ser-151' of FBXW5 during the G1/S transition, leading to inhibit FBXW5 ability to ubiquitinate SASS6. Its central role in centriole replication suggests a possible role in tumorigenesis, centrosome aberrations being frequently observed in tumors. Also involved in trophoblast differentiation by phosphorylating HAND1, leading to disrupt the interaction between HAND1 and MDFIC and activate HAND1. Phosphorylates CDC25C and CHEK2.[7] [8] [9] [10] [11] [12]

Publication Abstract from PubMed

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.

Structural and Functional Analyses of the FAM46C/Plk4 Complex.,Chen H, Lu D, Shang G, Gao G, Zhang X Structure. 2020 May 12. pii: S0969-2126(20)30169-6. doi:, 10.1016/j.str.2020.04.023. PMID:32433990[13]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Kuchta K, Muszewska A, Knizewski L, Steczkiewicz K, Wyrwicz LS, Pawlowski K, Rychlewski L, Ginalski K. FAM46 proteins are novel eukaryotic non-canonical poly(A) polymerases. Nucleic Acids Res. 2016 May 5;44(8):3534-48. doi: 10.1093/nar/gkw222. Epub 2016, Apr 7. PMID:27060136 doi:http://dx.doi.org/10.1093/nar/gkw222
  2. ↑ Mroczek S, Chlebowska J, Kulinski TM, Gewartowska O, Gruchota J, Cysewski D, Liudkovska V, Borsuk E, Nowis D, Dziembowski A. The non-canonical poly(A) polymerase FAM46C acts as an onco-suppressor in multiple myeloma. Nat Commun. 2017 Sep 20;8(1):619. doi: 10.1038/s41467-017-00578-5. PMID:28931820 doi:http://dx.doi.org/10.1038/s41467-017-00578-5
  3. ↑ Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011 Apr 28;472(7344):481-5. doi: 10.1038/nature09907. Epub 2011 Apr 10. PMID:21478870 doi:10.1038/nature09907
  4. ↑ Gomez-Ferreria MA, Rath U, Buster DW, Chanda SK, Caldwell JS, Rines DR, Sharp DJ. Human Cep192 is required for mitotic centrosome and spindle assembly. Curr Biol. 2007 Nov 20;17(22):1960-6. doi: 10.1016/j.cub.2007.10.019. Epub 2007, Nov 1. PMID:17980596 doi:http://dx.doi.org/10.1016/j.cub.2007.10.019
  5. ↑ Zhu F, Lawo S, Bird A, Pinchev D, Ralph A, Richter C, Muller-Reichert T, Kittler R, Hyman AA, Pelletier L. The mammalian SPD-2 ortholog Cep192 regulates centrosome biogenesis. Curr Biol. 2008 Jan 22;18(2):136-41. doi: 10.1016/j.cub.2007.12.055. PMID:18207742 doi:http://dx.doi.org/10.1016/j.cub.2007.12.055
  6. ↑ Joukov V, Walter JC, De Nicolo A. The Cep192-organized aurora A-Plk1 cascade is essential for centrosome cycle and bipolar spindle assembly. Mol Cell. 2014 Aug 21;55(4):578-91. doi: 10.1016/j.molcel.2014.06.016. Epub 2014 , Jul 17. PMID:25042804 doi:http://dx.doi.org/10.1016/j.molcel.2014.06.016
  7. ↑ Bettencourt-Dias M, Rodrigues-Martins A, Carpenter L, Riparbelli M, Lehmann L, Gatt MK, Carmo N, Balloux F, Callaini G, Glover DM. SAK/PLK4 is required for centriole duplication and flagella development. Curr Biol. 2005 Dec 20;15(24):2199-207. Epub 2005 Dec 1. PMID:16326102 doi:http://dx.doi.org/10.1016/j.cub.2005.11.042
  8. ↑ Habedanck R, Stierhof YD, Wilkinson CJ, Nigg EA. The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol. 2005 Nov;7(11):1140-6. PMID:16244668 doi:http://dx.doi.org/10.1038/ncb1320
  9. ↑ Kleylein-Sohn J, Westendorf J, Le Clech M, Habedanck R, Stierhof YD, Nigg EA. Plk4-induced centriole biogenesis in human cells. Dev Cell. 2007 Aug;13(2):190-202. PMID:17681131 doi:http://dx.doi.org/10.1016/j.devcel.2007.07.002
  10. ↑ Bonni S, Ganuelas ML, Petrinac S, Hudson JW. Human Plk4 phosphorylates Cdc25C. Cell Cycle. 2008 Feb 15;7(4):545-7. Epub 2007 Nov 25. PMID:18239451
  11. ↑ Petrinac S, Ganuelas ML, Bonni S, Nantais J, Hudson JW. Polo-like kinase 4 phosphorylates Chk2. Cell Cycle. 2009 Jan 15;8(2):327-9. PMID:19164942
  12. ↑ Puklowski A, Homsi Y, Keller D, May M, Chauhan S, Kossatz U, Grunwald V, Kubicka S, Pich A, Manns MP, Hoffmann I, Gonczy P, Malek NP. The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication. Nat Cell Biol. 2011 Jul 3;13(8):1004-9. doi: 10.1038/ncb2282. PMID:21725316 doi:http://dx.doi.org/10.1038/ncb2282
  13. ↑ Chen H, Lu D, Shang G, Gao G, Zhang X. Structural and Functional Analyses of the FAM46C/Plk4 Complex. Structure. 2020 May 12. pii: S0969-2126(20)30169-6. doi:, 10.1016/j.str.2020.04.023. PMID:32433990 doi:http://dx.doi.org/10.1016/j.str.2020.04.023

6w3j, resolution 4.38Å

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