6bn1

From Proteopedia

(Difference between revisions)

Revision as of 08:03, 21 March 2018

Salvador Hippo SARAH domain complex

Structural highlights

6bn1 is a 2 chain structure with sequence from Drome. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	hpo, CG11228 (DROME), sav, SHRP, CG33193 (DROME)
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[HIPPO_DROME] Plays a key role in the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that 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 Hippo (Hpo), in complex with its regulatory protein Salvador (Sav), phosphorylates and activates Warts (Wts) in complex with its regulatory protein Mats, which in turn phosphorylates and inactivates the Yorkie (Yki) oncoprotein. The Hippo/SWH signaling pathway inhibits the activity of the transcriptional complex formed by Scalloped (sd) and Yki and the target genes of this pathway include cyclin-E (cycE), diap1 and bantam. Phosphorylates Sav, Wts and Th/DIAP1. Regulates the level of Th/DIAP1 apoptosis inhibitor.^[1] ^[2] ^[3] ^[4] ^[5] [SAV_DROME] Plays a key role in the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that 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 Hippo (Hpo), in complex with its regulatory protein Salvador (Sav), phosphorylates and activates Warts (Wts) in complex with its regulatory protein Mats, which in turn phosphorylates and inactivates the Yorkie (Yki) oncoprotein. The Hippo/SWH signaling pathway inhibits the activity of the transcriptional complex formed by Scalloped (sd) and Yki and the target genes of this pathway include cyclin-E (cycE), diap1 and bantam. Required for cell cycle exit in eye imaginal disk and hid-induced apoptotic cell deaths that are part of normal retinal development. Activation of Drice in eye imaginal disk by either Hid or Rpr is almost completely blocked by Sav expression.^[6] ^[7] ^[8]

Publication Abstract from PubMed

The Hippo pathway controls cell proliferation and differentiation through the precisely tuned activity of a core kinase cassette. The activity of Hippo kinase is modulated by interactions between its C-terminal coiled-coil, termed the SARAH domain, and the SARAH domains of either dRassF or Salvador. Here, we wanted to understand the molecular basis of SARAH domain mediated interactions and their influence on Hippo kinase activity. We focused on Salvador, a positive effector of Hippo activity and the least well characterized SARAH domain-containing protein. We determined the crystal structure of a complex between Salvador and Hippo SARAH domains from Drosophila. This structure provided insight into the organization of the Salvador SARAH domain including a folded N-terminal extension that expands the binding interface with Hippo SARAH domain. We also found this extension improves the solubility of Salvador SARAH domain, enhances binding to Hippo, and is unique to Salvador. We therefore suggest expanding the definition of the Salvador SARAH domain to include this extended region. The heterodimeric assembly observed in the crystal was confirmed by crosslinked mass spectrometry and provided a structural basis for the mutually exclusive interactions of Hippo with either dRassF or Salvador. Of note, Salvador influenced the kinase activity of Mst2, the mammalian Hippo homolog. In co-transfected HEK293T cells, human Salvador increased the levels of Mst2 autophosphorylation and Mst2-mediated phosphorylation of select substrates, whereas Salvador SARAH domain inhibited Mst2 autophosphorylation in vitro. These results suggest Salvador enhances the effects of Hippo kinase activity at multiple points in the Hippo pathway.

Salvador has an extended SARAH domain that mediates binding to Hippo kinase.,Cairns L, Tran T, Fowl BH, Patterson A, Kim YJ, Bothner B, Kavran JM J Biol Chem. 2018 Mar 8. pii: RA117.000923. doi: 10.1074/jbc.RA117.000923. PMID:29519817^[9]

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

References

↑ Wu S, Huang J, Dong J, Pan D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell. 2003 Aug 22;114(4):445-56. PMID:12941273
↑ Harvey KF, Pfleger CM, Hariharan IK. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell. 2003 Aug 22;114(4):457-67. PMID:12941274
↑ Udan RS, Kango-Singh M, Nolo R, Tao C, Halder G. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol. 2003 Oct;5(10):914-20. doi: 10.1038/ncb1050. Epub 2003 Sep 21. PMID:14502294 doi:http://dx.doi.org/10.1038/ncb1050
↑ Pantalacci S, Tapon N, Leopold P. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol. 2003 Oct;5(10):921-7. Epub 2003 Sep 21. PMID:14502295 doi:http://dx.doi.org/10.1038/ncb1051
↑ Jia J, Zhang W, Wang B, Trinko R, Jiang J. The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis. Genes Dev. 2003 Oct 15;17(20):2514-9. PMID:14561774 doi:http://dx.doi.org/10.1101/gad.1134003
↑ Tapon N, Harvey KF, Bell DW, Wahrer DC, Schiripo TA, Haber D, Hariharan IK. salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell. 2002 Aug 23;110(4):467-78. PMID:12202036
↑ Kango-Singh M, Nolo R, Tao C, Verstreken P, Hiesinger PR, Bellen HJ, Halder G. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development. 2002 Dec;129(24):5719-30. PMID:12421711
↑ Harvey KF, Pfleger CM, Hariharan IK. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell. 2003 Aug 22;114(4):457-67. PMID:12941274
↑ Cairns L, Tran T, Fowl BH, Patterson A, Kim YJ, Bothner B, Kavran JM. Salvador has an extended SARAH domain that mediates binding to Hippo kinase. J Biol Chem. 2018 Mar 8. pii: RA117.000923. doi: 10.1074/jbc.RA117.000923. PMID:29519817 doi:http://dx.doi.org/10.1074/jbc.RA117.000923

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6bn1"

@@ Line 3: / Line 3: @@
 <StructureSection load='6bn1' size='340' side='right' caption='[[6bn1]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6bn1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BN1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BN1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6bn1]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Drome Drome]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BN1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BN1 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">hpo, CG11228 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7227 DROME]), sav, SHRP, CG33193 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7227 DROME])</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=6bn1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bn1 OCA], [http://pdbe.org/6bn1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bn1 RCSB], [http://www.ebi.ac.uk/pdbsum/6bn1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bn1 ProSAT]</span></td></tr>
@@ Line 10: / Line 11: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/HIPPO_DROME HIPPO_DROME]] Plays a key role in the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that 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 Hippo (Hpo), in complex with its regulatory protein Salvador (Sav), phosphorylates and activates Warts (Wts) in complex with its regulatory protein Mats, which in turn phosphorylates and inactivates the Yorkie (Yki) oncoprotein. The Hippo/SWH signaling pathway inhibits the activity of the transcriptional complex formed by Scalloped (sd) and Yki and the target genes of this pathway include cyclin-E (cycE), diap1 and bantam. Phosphorylates Sav, Wts and Th/DIAP1. Regulates the level of Th/DIAP1 apoptosis inhibitor.<ref>PMID:12941273</ref> <ref>PMID:12941274</ref> <ref>PMID:14502294</ref> <ref>PMID:14502295</ref> <ref>PMID:14561774</ref>  [[http://www.uniprot.org/uniprot/SAV_DROME SAV_DROME]] Plays a key role in the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that 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 Hippo (Hpo), in complex with its regulatory protein Salvador (Sav), phosphorylates and activates Warts (Wts) in complex with its regulatory protein Mats, which in turn phosphorylates and inactivates the Yorkie (Yki) oncoprotein. The Hippo/SWH signaling pathway inhibits the activity of the transcriptional complex formed by Scalloped (sd) and Yki and the target genes of this pathway include cyclin-E (cycE), diap1 and bantam. Required for cell cycle exit in eye imaginal disk and hid-induced apoptotic cell deaths that are part of normal retinal development. Activation of Drice in eye imaginal disk by either Hid or Rpr is almost completely blocked by Sav expression.<ref>PMID:12202036</ref> <ref>PMID:12421711</ref> <ref>PMID:12941274</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The Hippo pathway controls cell proliferation and differentiation through the precisely tuned activity of a core kinase cassette. The activity of Hippo kinase is modulated by interactions between its C-terminal coiled-coil, termed the SARAH domain, and the SARAH domains of either dRassF or Salvador. Here, we wanted to understand the molecular basis of SARAH domain mediated interactions and their influence on Hippo kinase activity. We focused on Salvador, a positive effector of Hippo activity and the least well characterized SARAH domain-containing protein. We determined the crystal structure of a complex between Salvador and Hippo SARAH domains from Drosophila. This structure provided insight into the organization of the Salvador SARAH domain including a folded N-terminal extension that expands the binding interface with Hippo SARAH domain. We also found this extension improves the solubility of Salvador SARAH domain, enhances binding to Hippo, and is unique to Salvador. We therefore suggest expanding the definition of the Salvador SARAH domain to include this extended region. The heterodimeric assembly observed in the crystal was confirmed by crosslinked mass spectrometry and provided a structural basis for the mutually exclusive interactions of Hippo with either dRassF or Salvador. Of note, Salvador influenced the kinase activity of Mst2, the mammalian Hippo homolog. In co-transfected HEK293T cells, human Salvador increased the levels of Mst2 autophosphorylation and Mst2-mediated phosphorylation of select substrates, whereas Salvador SARAH domain inhibited Mst2 autophosphorylation in vitro. These results suggest Salvador enhances the effects of Hippo kinase activity at multiple points in the Hippo pathway.
+Salvador has an extended SARAH domain that mediates binding to Hippo kinase.,Cairns L, Tran T, Fowl BH, Patterson A, Kim YJ, Bothner B, Kavran JM J Biol Chem. 2018 Mar 8. pii: RA117.000923. doi: 10.1074/jbc.RA117.000923. PMID:29519817<ref>PMID:29519817</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6bn1" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Drome]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Cairns, L]]

6bn1

From Proteopedia

Revision as of 08:03, 21 March 2018

Salvador Hippo SARAH domain complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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