4ifc

Crystal Structure of ADP-bound Human PRPF4B kinase domainCrystal Structure of ADP-bound Human PRPF4B kinase domain

Structural highlights

4ifc is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.13Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PRP4K_HUMAN Serine/threonine kinase involved in spliceosomal assembly as well as mitosis and signaling regulation (PubMed:10799319, PubMed:12077342, PubMed:17513757, PubMed:17998396). Connects chromatin mediated regulation of transcription and pre-mRNA splicing (PubMed:12077342). During spliceosomal assembly, interacts with and phosphorylates PRPF6 and PRPF31, components of the U4/U6-U5 tri-small nuclear ribonucleoprotein (snRNP), to facilitate the formation of the spliceosome B complex. Plays a role in regulating transcription and the spindle assembly checkpoint (SAC) (PubMed:20118938). Associates with U5 snRNP and NCOR1 deacetylase complexes which may allow a coordination of pre-mRNA splicing with chromatin remodeling events involved in transcriptional regulation (PubMed:12077342). Associates and probably phosphorylates SMARCA4 and NCOR1 (PubMed:12077342). Phosphorylates SRSF1 (PubMed:11418604). Associates with kinetochores during mitosis and is necessary for recruitment and maintenance of the checkpoint proteins such as MAD1L1 and MAD12L1 at the kinetochores (PubMed:17998396). Phosphorylates and regulates the activity of the transcription factors such as ELK1 and KLF13 (PubMed:10799319, PubMed:17513757). Phosphorylates nuclear YAP1 and WWTR1/TAZ which induces nuclear exclusion and regulates Hippo signaling pathway, involved in tissue growth control (PubMed:29695716).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

PRP4 kinase is known for its roles in regulating pre-mRNA splicing and beyond. Therefore, a wider spectrum of PRP4 kinase substrates could be expected. The role of PRP4 kinase in cancer is also yet to be fully elucidated. Attaining specific and potent PRP4 inhibitors would greatly facilitate the study of PRP4 biological function and its validation as a credible cancer target. In this report, we verified the requirement of enzymatic activity of PRP4 in regulating cancer cell growth and identified an array of potential novel substrates through orthogonal proteomics approaches. The ensuing effort in structural biology unveiled for the first time unique features of PRP4 kinase domain and its potential mode of interaction with a low molecular weight inhibitor. These results provide new and important information for further exploration of PRP4 kinase function in cancer.

Evaluation of cancer dependence and druggability of PRP4 kinase using cellular, biochemical, and structural approaches.,Gao Q, Mechin I, Kothari N, Guo Z, Deng G, Haas K, McManus J, Hoffmann D, Wang A, Wiederschain D, Rocnik J, Czechtizky W, Chen X, McLean L, Arlt H, Harper D, Liu F, Majid T, Patel V, Lengauer C, Garcia-Echeverria C, Zhang B, Cheng H, Dorsch M, Huang SM J Biol Chem. 2013 Sep 3. PMID:24003220^[8]

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

References

↑ Huang Y, Deng T, Winston BW. Characterization of hPRP4 kinase activation: potential role in signaling. Biochem Biophys Res Commun. 2000 May 10;271(2):456-63. PMID:10799319 doi:10.1006/bbrc.2000.2651
↑ Kojima T, Zama T, Wada K, Onogi H, Hagiwara M. Cloning of human PRP4 reveals interaction with Clk1. J Biol Chem. 2001 Aug 24;276(34):32247-56. PMID:11418604 doi:10.1074/jbc.M103790200
↑ Dellaire G, Makarov EM, Cowger JJ, Longman D, Sutherland HG, Lührmann R, Torchia J, Bickmore WA. Mammalian PRP4 kinase copurifies and interacts with components of both the U5 snRNP and the N-CoR deacetylase complexes. Mol Cell Biol. 2002 Jul;22(14):5141-56. PMID:12077342 doi:10.1128/MCB.22.14.5141-5156.2002
↑ Huang B, Ahn YT, McPherson L, Clayberger C, Krensky AM. Interaction of PRP4 with Kruppel-like factor 13 regulates CCL5 transcription. J Immunol. 2007 Jun 1;178(11):7081-7. PMID:17513757 doi:10.4049/jimmunol.178.11.7081
↑ Montembault E, Dutertre S, Prigent C, Giet R. PRP4 is a spindle assembly checkpoint protein required for MPS1, MAD1, and MAD2 localization to the kinetochores. J Cell Biol. 2007 Nov 19;179(4):601-9. PMID:17998396 doi:10.1083/jcb.200703133
↑ Schneider M, Hsiao HH, Will CL, Giet R, Urlaub H, Lührmann R. Human PRP4 kinase is required for stable tri-snRNP association during spliceosomal B complex formation. Nat Struct Mol Biol. 2010 Feb;17(2):216-21. PMID:20118938 doi:10.1038/nsmb.1718
↑ Cho YS, Zhu J, Li S, Wang B, Han Y, Jiang J. Regulation of Yki/Yap subcellular localization and Hpo signaling by a nuclear kinase PRP4K. Nat Commun. 2018 Apr 25;9(1):1657. PMID:29695716 doi:10.1038/s41467-018-04090-2
↑ Gao Q, Mechin I, Kothari N, Guo Z, Deng G, Haas K, McManus J, Hoffmann D, Wang A, Wiederschain D, Rocnik J, Czechtizky W, Chen X, McLean L, Arlt H, Harper D, Liu F, Majid T, Patel V, Lengauer C, Garcia-Echeverria C, Zhang B, Cheng H, Dorsch M, Huang SM. Evaluation of cancer dependence and druggability of PRP4 kinase using cellular, biochemical, and structural approaches. J Biol Chem. 2013 Sep 3. PMID:24003220 doi:10.1074/jbc.M113.473348

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OCA

[1] Huang Y, Deng T, Winston BW. Characterization of hPRP4 kinase activation: potential role in signaling. Biochem Biophys Res Commun. 2000 May 10;271(2):456-63. PMID:10799319 doi:10.1006/bbrc.2000.2651

[2] Kojima T, Zama T, Wada K, Onogi H, Hagiwara M. Cloning of human PRP4 reveals interaction with Clk1. J Biol Chem. 2001 Aug 24;276(34):32247-56. PMID:11418604 doi:10.1074/jbc.M103790200

[3] Dellaire G, Makarov EM, Cowger JJ, Longman D, Sutherland HG, Lührmann R, Torchia J, Bickmore WA. Mammalian PRP4 kinase copurifies and interacts with components of both the U5 snRNP and the N-CoR deacetylase complexes. Mol Cell Biol. 2002 Jul;22(14):5141-56. PMID:12077342 doi:10.1128/MCB.22.14.5141-5156.2002

[4] Huang B, Ahn YT, McPherson L, Clayberger C, Krensky AM. Interaction of PRP4 with Kruppel-like factor 13 regulates CCL5 transcription. J Immunol. 2007 Jun 1;178(11):7081-7. PMID:17513757 doi:10.4049/jimmunol.178.11.7081

[5] Montembault E, Dutertre S, Prigent C, Giet R. PRP4 is a spindle assembly checkpoint protein required for MPS1, MAD1, and MAD2 localization to the kinetochores. J Cell Biol. 2007 Nov 19;179(4):601-9. PMID:17998396 doi:10.1083/jcb.200703133

[6] Schneider M, Hsiao HH, Will CL, Giet R, Urlaub H, Lührmann R. Human PRP4 kinase is required for stable tri-snRNP association during spliceosomal B complex formation. Nat Struct Mol Biol. 2010 Feb;17(2):216-21. PMID:20118938 doi:10.1038/nsmb.1718

[7] Cho YS, Zhu J, Li S, Wang B, Han Y, Jiang J. Regulation of Yki/Yap subcellular localization and Hpo signaling by a nuclear kinase PRP4K. Nat Commun. 2018 Apr 25;9(1):1657. PMID:29695716 doi:10.1038/s41467-018-04090-2

[8] Gao Q, Mechin I, Kothari N, Guo Z, Deng G, Haas K, McManus J, Hoffmann D, Wang A, Wiederschain D, Rocnik J, Czechtizky W, Chen X, McLean L, Arlt H, Harper D, Liu F, Majid T, Patel V, Lengauer C, Garcia-Echeverria C, Zhang B, Cheng H, Dorsch M, Huang SM. Evaluation of cancer dependence and druggability of PRP4 kinase using cellular, biochemical, and structural approaches. J Biol Chem. 2013 Sep 3. PMID:24003220 doi:10.1074/jbc.M113.473348

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