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Kinase Domain Insertions Define Distinct Roles of CLK Kinases in SR Protein Phosphorylation
Splicing requires reversible phosphorylation of serine/arginine-rich (SR) proteins, which direct splice site selection in eukaryotic mRNA. These phosphorylation events are dependent on SR protein (SRPK) and cdc2-like kinase (CLK) families. SRPK1 phosphorylation of splicing factors is restricted by a...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667211/ https://www.ncbi.nlm.nih.gov/pubmed/19278650 http://dx.doi.org/10.1016/j.str.2008.12.023 |
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author | Bullock, Alex N. Das, Sanjan Debreczeni, Judit É. Rellos, Peter Fedorov, Oleg Niesen, Frank H. Guo, Kunde Papagrigoriou, Evangelos Amos, Ann L. Cho, Suhyung Turk, Benjamin E. Ghosh, Gourisankar Knapp, Stefan |
author_facet | Bullock, Alex N. Das, Sanjan Debreczeni, Judit É. Rellos, Peter Fedorov, Oleg Niesen, Frank H. Guo, Kunde Papagrigoriou, Evangelos Amos, Ann L. Cho, Suhyung Turk, Benjamin E. Ghosh, Gourisankar Knapp, Stefan |
author_sort | Bullock, Alex N. |
collection | PubMed |
description | Splicing requires reversible phosphorylation of serine/arginine-rich (SR) proteins, which direct splice site selection in eukaryotic mRNA. These phosphorylation events are dependent on SR protein (SRPK) and cdc2-like kinase (CLK) families. SRPK1 phosphorylation of splicing factors is restricted by a specific docking interaction whereas CLK activity is less constrained. To understand functional differences between splicing factor targeting kinases, we determined crystal structures of CLK1 and CLK3. Intriguingly, in CLKs the SRPK1 docking site is blocked by insertion of a previously unseen helix αH. In addition, substrate docking grooves present in related mitogen activating protein kinases (MAPKs) are inaccessible due to a CLK specific β7/8-hairpin insert. Thus, the unconstrained substrate interaction together with the determined active-site mediated substrate specificity allows CLKs to complete the functionally important hyperphosphorylation of splicing factors like ASF/SF2. In addition, despite high sequence conservation, we identified inhibitors with surprising isoform specificity for CLK1 over CLK3. |
format | Text |
id | pubmed-2667211 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-26672112009-04-22 Kinase Domain Insertions Define Distinct Roles of CLK Kinases in SR Protein Phosphorylation Bullock, Alex N. Das, Sanjan Debreczeni, Judit É. Rellos, Peter Fedorov, Oleg Niesen, Frank H. Guo, Kunde Papagrigoriou, Evangelos Amos, Ann L. Cho, Suhyung Turk, Benjamin E. Ghosh, Gourisankar Knapp, Stefan Structure Article Splicing requires reversible phosphorylation of serine/arginine-rich (SR) proteins, which direct splice site selection in eukaryotic mRNA. These phosphorylation events are dependent on SR protein (SRPK) and cdc2-like kinase (CLK) families. SRPK1 phosphorylation of splicing factors is restricted by a specific docking interaction whereas CLK activity is less constrained. To understand functional differences between splicing factor targeting kinases, we determined crystal structures of CLK1 and CLK3. Intriguingly, in CLKs the SRPK1 docking site is blocked by insertion of a previously unseen helix αH. In addition, substrate docking grooves present in related mitogen activating protein kinases (MAPKs) are inaccessible due to a CLK specific β7/8-hairpin insert. Thus, the unconstrained substrate interaction together with the determined active-site mediated substrate specificity allows CLKs to complete the functionally important hyperphosphorylation of splicing factors like ASF/SF2. In addition, despite high sequence conservation, we identified inhibitors with surprising isoform specificity for CLK1 over CLK3. Cell Press 2009-03-11 /pmc/articles/PMC2667211/ /pubmed/19278650 http://dx.doi.org/10.1016/j.str.2008.12.023 Text en © 2009 ELL & Excerpta Medica. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license |
spellingShingle | Article Bullock, Alex N. Das, Sanjan Debreczeni, Judit É. Rellos, Peter Fedorov, Oleg Niesen, Frank H. Guo, Kunde Papagrigoriou, Evangelos Amos, Ann L. Cho, Suhyung Turk, Benjamin E. Ghosh, Gourisankar Knapp, Stefan Kinase Domain Insertions Define Distinct Roles of CLK Kinases in SR Protein Phosphorylation |
title | Kinase Domain Insertions Define Distinct Roles of CLK Kinases in SR Protein Phosphorylation |
title_full | Kinase Domain Insertions Define Distinct Roles of CLK Kinases in SR Protein Phosphorylation |
title_fullStr | Kinase Domain Insertions Define Distinct Roles of CLK Kinases in SR Protein Phosphorylation |
title_full_unstemmed | Kinase Domain Insertions Define Distinct Roles of CLK Kinases in SR Protein Phosphorylation |
title_short | Kinase Domain Insertions Define Distinct Roles of CLK Kinases in SR Protein Phosphorylation |
title_sort | kinase domain insertions define distinct roles of clk kinases in sr protein phosphorylation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667211/ https://www.ncbi.nlm.nih.gov/pubmed/19278650 http://dx.doi.org/10.1016/j.str.2008.12.023 |
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