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5k26

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Structure of the SH3 domain of MLK3 bound to peptide generated from phage display

Structural highlights

5k26 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 1.2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

M3K11_HUMAN Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Mixed-lineage kinase 3 (MLK3; also known as MAP3K11) is a Ser/Thr protein kinase widely expressed in normal and cancerous tissues, including brain, lung, liver, heart, and skeletal muscle tissues. Its Src homology 3 (SH3) domain has been implicated in MLK3 autoinhibition and interactions with other proteins, including those from viruses. The MLK3 SH3 domain contains a six-amino-acid insert corresponding to the n-Src insert, suggesting that MLK3 may bind additional peptides. Here, affinity selection of a phage-displayed combinatorial peptide library for MLK3's SH3 domain yielded a 13-mer peptide, designated "MLK3 SH3-interacting peptide" (MIP). Unlike most SH3 domain peptide ligands, MIP contained a single proline. The 1.2-A crystal structure of the MIP-bound SH3 domain revealed that the peptide adopts a beta-hairpin shape, and comparison with a 1.5-A apo SH3 domain structure disclosed that the n-Src loop in SH3 undergoes an MIP-induced conformational change. A 1.5-A structure of the MLK3 SH3 domain bound to a canonical proline-rich peptide from hepatitis C virus nonstructural 5A (NS5A) protein revealed that it and MIP bind the SH3 domain at two distinct sites, but biophysical analyses suggested that the two peptides compete with each other for SH3 binding. Moreover, SH3 domains of MLK1 and MLK4, but not MLK2, also bound MIP, suggesting that the MLK1-4 family may be differentially regulated through their SH3 domains. In summary, we have identified two distinct peptide-binding sites in the SH3 domain of MLK3, providing critical insights into mechanisms of ligand binding by the MLK family of kinases.

Identification of two distinct peptide-binding pockets in the SH3 domain of human mixed-lineage kinase 3.,Kokoszka ME, Kall SL, Khosla S, McGinnis JE, Lavie A, Kay BK J Biol Chem. 2018 Aug 31;293(35):13553-13565. doi: 10.1074/jbc.RA117.000262. Epub, 2018 Jul 6. PMID:29980598^[5]

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

References

↑ Swenson KI, Winkler KE, Means AR. A new identity for MLK3 as an NIMA-related, cell cycle-regulated kinase that is localized near centrosomes and influences microtubule organization. Mol Biol Cell. 2003 Jan;14(1):156-72. PMID:12529434 doi:http://dx.doi.org/10.1091/mbc.E02-02-0115
↑ Chadee DN, Kyriakis JM. MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation. Nat Cell Biol. 2004 Aug;6(8):770-6. Epub 2004 Jul 18. PMID:15258589 doi:http://dx.doi.org/10.1038/ncb1152
↑ Gallo KA, Mark MR, Scadden DT, Wang Z, Gu Q, Godowski PJ. Identification and characterization of SPRK, a novel src-homology 3 domain-containing proline-rich kinase with serine/threonine kinase activity. J Biol Chem. 1994 May 27;269(21):15092-100. PMID:8195146
↑ Tibbles LA, Ing YL, Kiefer F, Chan J, Iscove N, Woodgett JR, Lassam NJ. MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6. EMBO J. 1996 Dec 16;15(24):7026-35. PMID:9003778
↑ Kokoszka ME, Kall SL, Khosla S, McGinnis JE, Lavie A, Kay BK. Identification of two distinct peptide-binding pockets in the SH3 domain of human mixed-lineage kinase 3. J Biol Chem. 2018 Aug 31;293(35):13553-13565. doi: 10.1074/jbc.RA117.000262. Epub, 2018 Jul 6. PMID:29980598 doi:http://dx.doi.org/10.1074/jbc.RA117.000262

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/5k26"

Categories: Homo sapiens | Large Structures | Kall SK | Lavie A

@@ Line 1: / Line 1: @@
 ==Structure of the SH3 domain of MLK3 bound to peptide generated from phage display==
-<StructureSection load='5k26' size='340' side='right' caption='[[5k26]], [[Resolution|resolution]] 1.20&Aring;' scene=''>
+<StructureSection load='5k26' size='340' side='right'caption='[[5k26]], [[Resolution|resolution]] 1.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5k26]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K26 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5K26 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5k26]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K26 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5K26 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.2&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5k28|5k28]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAP3K11, MLK3, PTK1, SPRK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5k26 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k26 OCA], [https://pdbe.org/5k26 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5k26 RCSB], [https://www.ebi.ac.uk/pdbsum/5k26 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5k26 ProSAT]</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=5k26 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k26 OCA], [http://pdbe.org/5k26 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k26 RCSB], [http://www.ebi.ac.uk/pdbsum/5k26 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k26 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/M3K11_HUMAN M3K11_HUMAN]] Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle.<ref>PMID:12529434</ref> <ref>PMID:15258589</ref> <ref>PMID:8195146</ref> <ref>PMID:9003778</ref>
+[https://www.uniprot.org/uniprot/M3K11_HUMAN M3K11_HUMAN] Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle.<ref>PMID:12529434</ref> <ref>PMID:15258589</ref> <ref>PMID:8195146</ref> <ref>PMID:9003778</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Kall, S K]]
+[[Category: Large Structures]]
-[[Category: Lavie, A]]
+[[Category: Kall SK]]
-[[Category: Mlk3]]
+[[Category: Lavie A]]
-[[Category: Phage display]]
-[[Category: Sh3]]
-[[Category: Signalling protein]]
-[[Category: Transferase]]

5k26

From Proteopedia

Current revision

Structure of the SH3 domain of MLK3 bound to peptide generated from phage display

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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