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{{STRUCTURE_4lg4|  PDB=4lg4  |  SCENE=  }}
==Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5==
===Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5===
<StructureSection load='4lg4' size='340' side='right' caption='[[4lg4]], [[Resolution|resolution]] 2.42&Aring;' scene=''>
{{ABSTRACT_PUBMED_23972470}}
== Structural highlights ==
<table><tr><td colspan='2'>[[4lg4]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LG4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LG4 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lgd|4lgd]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">STK3, KRS1, MST2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4lg4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lg4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lg4 RCSB], [http://www.ebi.ac.uk/pdbsum/4lg4 PDBsum]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The tumor-suppressive Hippo pathway controls tissue homeostasis through balancing cell proliferation and apoptosis. Activation of the kinases Mst1 and Mst2 (Mst1/2) is a key upstream event in this pathway and remains poorly understood. Mst1/2 and their critical regulators RASSFs contain Salvador/RASSF1A/Hippo (SARAH) domains that can homo- and heterodimerize. Here, we report the crystal structures of human Mst2 alone and bound to RASSF5. Mst2 undergoes activation through transautophosphorylation at its activation loop, which requires SARAH-mediated homodimerization. RASSF5 disrupts Mst2 homodimer and blocks Mst2 autoactivation. Binding of RASSF5 to already activated Mst2, however, does not inhibit its kinase activity. Thus, RASSF5 can act as an inhibitor or a potential positive regulator of Mst2, depending on whether it binds to Mst2 before or after activation-loop phosphorylation. We propose that these temporally sensitive functions of RASSFs enable the Hippo pathway to respond to and integrate diverse cellular signals.


==Function==
Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5.,Ni L, Li S, Yu J, Min J, Brautigam CA, Tomchick DR, Pan D, Luo X Structure. 2013 Aug 20. pii: S0969-2126(13)00258-X. doi:, 10.1016/j.str.2013.07.008. PMID:23972470<ref>PMID:23972470</ref>
[[http://www.uniprot.org/uniprot/STK3_HUMAN STK3_HUMAN]] Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation. Phosphorylates NKX2-1 (By similarity). Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosome, and its ability to phosphorylate CROCC and CEP250. In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38.<ref>PMID:8566796</ref> <ref>PMID:8816758</ref> <ref>PMID:15688006</ref> <ref>PMID:16930133</ref> <ref>PMID:18328708</ref> <ref>PMID:18362890</ref> <ref>PMID:19525978</ref> <ref>PMID:20212043</ref> <ref>PMID:21076410</ref> <ref>PMID:21104395</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[4lg4]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LG4 OCA].
</div>


==Reference==
==See Also==
<ref group="xtra">PMID:023972470</ref><references group="xtra"/><references/>
*[[Serine/threonine protein kinase|Serine/threonine protein kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Luo, X.]]
[[Category: Luo, X]]
[[Category: Ni, L.]]
[[Category: Ni, L]]
[[Category: Tomchick, D R.]]
[[Category: Tomchick, D R]]
[[Category: Dimerization]]
[[Category: Dimerization]]
[[Category: Hippo]]
[[Category: Hippo]]
[[Category: Mst autoactivation]]
[[Category: Mst autoactivation]]
[[Category: Signaling protein]]
[[Category: Signaling protein]]

Revision as of 17:42, 21 December 2014

Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5

Structural highlights

4lg4 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:STK3, KRS1, MST2 (Homo sapiens)
Activity:Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:FirstGlance, OCA, RCSB, PDBsum

Publication Abstract from PubMed

The tumor-suppressive Hippo pathway controls tissue homeostasis through balancing cell proliferation and apoptosis. Activation of the kinases Mst1 and Mst2 (Mst1/2) is a key upstream event in this pathway and remains poorly understood. Mst1/2 and their critical regulators RASSFs contain Salvador/RASSF1A/Hippo (SARAH) domains that can homo- and heterodimerize. Here, we report the crystal structures of human Mst2 alone and bound to RASSF5. Mst2 undergoes activation through transautophosphorylation at its activation loop, which requires SARAH-mediated homodimerization. RASSF5 disrupts Mst2 homodimer and blocks Mst2 autoactivation. Binding of RASSF5 to already activated Mst2, however, does not inhibit its kinase activity. Thus, RASSF5 can act as an inhibitor or a potential positive regulator of Mst2, depending on whether it binds to Mst2 before or after activation-loop phosphorylation. We propose that these temporally sensitive functions of RASSFs enable the Hippo pathway to respond to and integrate diverse cellular signals.

Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5.,Ni L, Li S, Yu J, Min J, Brautigam CA, Tomchick DR, Pan D, Luo X Structure. 2013 Aug 20. pii: S0969-2126(13)00258-X. doi:, 10.1016/j.str.2013.07.008. PMID:23972470[1]

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

See Also

References

  1. ↑ Ni L, Li S, Yu J, Min J, Brautigam CA, Tomchick DR, Pan D, Luo X. Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5. Structure. 2013 Aug 20. pii: S0969-2126(13)00258-X. doi:, 10.1016/j.str.2013.07.008. PMID:23972470 doi:10.1016/j.str.2013.07.008

4lg4, resolution 2.42Å

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