| Structural highlights
Function
SRPK1_HUMAN Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing. Plays a central role in the regulatory network for splicing, controlling the intranuclear distribution of splicing factors in interphase cells and the reorganization of nuclear speckles during mitosis. Can influence additional steps of mRNA maturation, as well as other cellular activities, such as chromatin reorganization in somatic and sperm cells and cell cycle progression. Isoform 2 phosphorylates SFRS2, ZRSR2, LBR and PRM1. Isoform 2 phosphorylates SRSF1 using a directional (C-terminal to N-terminal) and a dual-track mechanism incorporating both processive phosphorylation (in which the kinase stays attached to the substrate after each round of phosphorylation) and distributive phosphorylation steps (in which the kinase and substrate dissociate after each phosphorylation event). The RS domain of SRSF1 binds first to a docking groove in the large lobe of the kinase domain of SRPK1. This induces certain structural changes in SRPK1 and/or RRM2 domain of SRSF1, allowing RRM2 to bind the kinase and initiate phosphorylation. The cycles continue for several phosphorylation steps in a processive manner (steps 1-8) until the last few phosphorylation steps (approximately steps 9-12). During that time, a mechanical stress induces the unfolding of the beta-4 motif in RRM2, which then docks at the docking groove of SRPK1. This also signals RRM2 to begin to dissociate, which facilitates SRSF1 dissociation after phosphorylation is completed. Isoform 2 can mediate hepatitis B virus (HBV) core protein phosphorylation. It plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles. Isoform 1 and isoform 2 can induce splicing of exon 10 in MAPT/TAU. The ratio of isoform 1/isoform 2 plays a decisive role in determining cell fate in K-562 leukaemic cell line: isoform 2 favors proliferation where as isoform 1 favors differentiation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]
Publication Abstract from PubMed
Serine-arginine (SR) protein kinases (SRPKs) regulate the functions of the SR-rich splicing factors by phosphorylating multiple serines within their C-terminal arginine-serine-rich domains. Dysregulation of these phosphorylation events has been implicated in many diseases, suggesting SRPKs are potential therapeutic targets. In particular, aberrant SRPK1 expression alters the balances of proangiogenic (VEGF(165)) and antiangiogenic (VEGF(165)b) splicing isoforms of the key angiogenesis factor, vascular endothelial growth factor (VEGF), through the phosphorylation of prototypic SR protein SRSF1. Here, we report a protein-protein interaction (PPI) inhibitor of SRPKs, docking blocker of SRPK1 (DBS1), that specifically blocks a conserved substrate docking groove unique to SRPKs. DBS1 is a cell-permeable inhibitor that effectively inhibits the binding and phosphorylation of SRSF1 and subsequently switches VEGF splicing from the proangiogenic to the antiangiogenic isoform. Our findings thus provide a new direction for the development of SRPK inhibitors through targeting a unique PPI site to combat angiogenic diseases.
Protein-Protein Interaction Inhibitor of SRPKs Alters the Splicing Isoforms of VEGF and Inhibits Angiogenesis.,Li Q, Zeng C, Liu H, Yung KWY, Chen C, Xie Q, Zhang Y, Wan SWC, Mak BSW, Xia J, Xiong S, Ngo JCK iScience. 2021 Apr 20;24(5):102423. doi: 10.1016/j.isci.2021.102423. eCollection , 2021 May 21. PMID:33997701[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gui JF, Lane WS, Fu XD. A serine kinase regulates intracellular localization of splicing factors in the cell cycle. Nature. 1994 Jun 23;369(6482):678-82. PMID:8208298 doi:http://dx.doi.org/10.1038/369678a0
- ↑ Nikolakaki E, Kohen R, Hartmann AM, Stamm S, Georgatsou E, Giannakouros T. Cloning and characterization of an alternatively spliced form of SR protein kinase 1 that interacts specifically with scaffold attachment factor-B. J Biol Chem. 2001 Oct 26;276(43):40175-82. Epub 2001 Aug 16. PMID:11509566 doi:http://dx.doi.org/10.1074/jbc.M104755200
- ↑ Daub H, Blencke S, Habenberger P, Kurtenbach A, Dennenmoser J, Wissing J, Ullrich A, Cotten M. Identification of SRPK1 and SRPK2 as the major cellular protein kinases phosphorylating hepatitis B virus core protein. J Virol. 2002 Aug;76(16):8124-37. PMID:12134018
- ↑ Lee CG, Hague LK, Li H, Donnelly R. Identification of toposome, a novel multisubunit complex containing topoisomerase IIalpha. Cell Cycle. 2004 May;3(5):638-47. Epub 2004 May 4. PMID:15034300
- ↑ Tronchere H, Wang J, Fu XD. A protein related to splicing factor U2AF35 that interacts with U2AF65 and SR proteins in splicing of pre-mRNA. Nature. 1997 Jul 24;388(6640):397-400. PMID:9237760 doi:http://dx.doi.org/10.1038/41137
- ↑ Papoutsopoulou S, Nikolakaki E, Giannakouros T. SRPK1 and LBR protein kinases show identical substrate specificities. Biochem Biophys Res Commun. 1999 Feb 24;255(3):602-7. PMID:10049757 doi:http://dx.doi.org/10.1006/bbrc.1999.0249
- ↑ Papoutsopoulou S, Nikolakaki E, Chalepakis G, Kruft V, Chevaillier P, Giannakouros T. SR protein-specific kinase 1 is highly expressed in testis and phosphorylates protamine 1. Nucleic Acids Res. 1999 Jul 15;27(14):2972-80. PMID:10390541
- ↑ Aubol BE, Chakrabarti S, Ngo J, Shaffer J, Nolen B, Fu XD, Ghosh G, Adams JA. Processive phosphorylation of alternative splicing factor/splicing factor 2. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12601-6. Epub 2003 Oct 10. PMID:14555757 doi:http://dx.doi.org/10.1073/pnas.1635129100
- ↑ Zheng Y, Fu XD, Ou JH. Suppression of hepatitis B virus replication by SRPK1 and SRPK2 via a pathway independent of the phosphorylation of the viral core protein. Virology. 2005 Nov 10;342(1):150-8. Epub 2005 Aug 24. PMID:16122776 doi:http://dx.doi.org/10.1016/j.virol.2005.07.030
- ↑ Ma CT, Velazquez-Dones A, Hagopian JC, Ghosh G, Fu XD, Adams JA. Ordered multi-site phosphorylation of the splicing factor ASF/SF2 by SRPK1. J Mol Biol. 2008 Feb 8;376(1):55-68. Epub 2007 Aug 21. PMID:18155240 doi:http://dx.doi.org/10.1016/j.jmb.2007.08.029
- ↑ Hagopian JC, Ma CT, Meade BR, Albuquerque CP, Ngo JC, Ghosh G, Jennings PA, Fu XD, Adams JA. Adaptable molecular interactions guide phosphorylation of the SR protein ASF/SF2 by SRPK1. J Mol Biol. 2008 Oct 17;382(4):894-909. doi: 10.1016/j.jmb.2008.07.055. Epub 2008, Jul 26. PMID:18687337 doi:http://dx.doi.org/10.1016/j.jmb.2008.07.055
- ↑ Huynh N, Ma CT, Giang N, Hagopian J, Ngo J, Adams J, Ghosh G. Allosteric interactions direct binding and phosphorylation of ASF/SF2 by SRPK1. Biochemistry. 2009 Dec 8;48(48):11432-40. doi: 10.1021/bi901107q. PMID:19886675 doi:http://dx.doi.org/10.1021/bi901107q
- ↑ Zhong XY, Ding JH, Adams JA, Ghosh G, Fu XD. Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones. Genes Dev. 2009 Feb 15;23(4):482-95. doi: 10.1101/gad.1752109. PMID:19240134 doi:http://dx.doi.org/10.1101/gad.1752109
- ↑ Ma CT, Hagopian JC, Ghosh G, Fu XD, Adams JA. Regiospecific phosphorylation control of the SR protein ASF/SF2 by SRPK1. J Mol Biol. 2009 Jul 24;390(4):618-34. Epub 2009 May 27. PMID:19477182 doi:http://dx.doi.org/S0022-2836(09)00623-8
- ↑ Sanidas I, Kotoula V, Ritou E, Daans J, Lenz C, Mairhofer M, Daniilidou M, Kolbus A, Kruft V, Ponsaerts P, Nikolakaki E. The ratio of SRPK1/SRPK1a regulates erythroid differentiation in K562 leukaemic cells. Biochim Biophys Acta. 2010 Dec;1803(12):1319-31. doi:, 10.1016/j.bbamcr.2010.07.008. Epub 2010 Aug 12. PMID:20708644 doi:http://dx.doi.org/10.1016/j.bbamcr.2010.07.008
- ↑ Ngo JC, Chakrabarti S, Ding JH, Velazquez-Dones A, Nolen B, Aubol BE, Adams JA, Fu XD, Ghosh G. Interplay between SRPK and Clk/Sty kinases in phosphorylation of the splicing factor ASF/SF2 is regulated by a docking motif in ASF/SF2. Mol Cell. 2005 Oct 7;20(1):77-89. PMID:16209947 doi:10.1016/j.molcel.2005.08.025
- ↑ Li Q, Zeng C, Liu H, Yung KWY, Chen C, Xie Q, Zhang Y, Wan SWC, Mak BSW, Xia J, Xiong S, Ngo JCK. Protein-Protein Interaction Inhibitor of SRPKs Alters the Splicing Isoforms of VEGF and Inhibits Angiogenesis. iScience. 2021 Apr 20;24(5):102423. PMID:33997701 doi:10.1016/j.isci.2021.102423
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