7l4j: Difference between revisions

Latest revision as of 15:37, 18 October 2023

Crystal structure of WT PPM1H phosphatase

Structural highlights

7l4j 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 2.451Å
Ligands:	MG
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PPM1H_HUMAN Dephosphorylates CDKN1B at 'Thr-187', thus removing a signal for proteasomal degradation.^[1]

Publication Abstract from PubMed

LRRK2 serine/threonine kinase is associated with inherited Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their switch 2 motif to control their interactions with effectors. Recent work has shown that the metal-dependent protein phosphatase PPM1H counteracts LRRK2 by dephosphorylating Rabs. PPM1H is highly selective for LRRK2 phosphorylated Rabs, and closely related PPM1J exhibits no activity towards substrates such as Rab8a phosphorylated at Thr72 (pThr72). Here, we have identified the molecular determinant of PPM1H specificity for Rabs. The crystal structure of PPM1H reveals a structurally conserved phosphatase fold that strikingly has evolved a 110-residue flap domain adjacent to the active site. The flap domain distantly resembles tudor domains that interact with histones in the context of epigenetics. Cellular assays, crosslinking and 3-D modelling suggest that the flap domain encodes the docking motif for phosphorylated Rabs. Consistent with this hypothesis, a PPM1J chimaera with the PPM1H flap domain dephosphorylates pThr72 of Rab8a both in vitro and in cellular assays. Therefore, PPM1H has acquired a Rab-specific interaction domain within a conserved phosphatase fold.

Structural basis for the specificity of PPM1H phosphatase for Rab GTPases.,Waschbusch D, Berndsen K, Lis P, Knebel A, Lam YP, Alessi DR, Khan AR EMBO Rep. 2021 Nov 4;22(11):e52675. doi: 10.15252/embr.202152675. Epub 2021 Sep, 28. PMID:34580980^[2]

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

References

↑ Lee-Hoeflich ST, Pham TQ, Dowbenko D, Munroe X, Lee J, Li L, Zhou W, Haverty PM, Pujara K, Stinson J, Chan SM, Eastham-Anderson J, Pandita A, Seshagiri S, Hoeflich KP, Turashvili G, Gelmon KA, Aparicio SA, Davis DP, Sliwkowski MX, Stern HM. PPM1H is a p27 phosphatase implicated in trastuzumab resistance. Cancer Discov. 2011 Sep;1(4):326-37. doi: 10.1158/2159-8290.CD-11-0062. Epub 2011, Jul 20. PMID:22586611 doi:https://dx.doi.org/10.1158/2159-8290.CD-11-0062
↑ Waschbusch D, Berndsen K, Lis P, Knebel A, Lam YP, Alessi DR, Khan AR. Structural basis for the specificity of PPM1H phosphatase for Rab GTPases. EMBO Rep. 2021 Nov 4;22(11):e52675. doi: 10.15252/embr.202152675. Epub 2021 Sep, 28. PMID:34580980 doi:https://dx.doi.org/10.15252/embr.202152675

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OCA

[1] Lee-Hoeflich ST, Pham TQ, Dowbenko D, Munroe X, Lee J, Li L, Zhou W, Haverty PM, Pujara K, Stinson J, Chan SM, Eastham-Anderson J, Pandita A, Seshagiri S, Hoeflich KP, Turashvili G, Gelmon KA, Aparicio SA, Davis DP, Sliwkowski MX, Stern HM. PPM1H is a p27 phosphatase implicated in trastuzumab resistance. Cancer Discov. 2011 Sep;1(4):326-37. doi: 10.1158/2159-8290.CD-11-0062. Epub 2011, Jul 20. PMID:22586611 doi:https://dx.doi.org/10.1158/2159-8290.CD-11-0062

[2] Waschbusch D, Berndsen K, Lis P, Knebel A, Lam YP, Alessi DR, Khan AR. Structural basis for the specificity of PPM1H phosphatase for Rab GTPases. EMBO Rep. 2021 Nov 4;22(11):e52675. doi: 10.15252/embr.202152675. Epub 2021 Sep, 28. PMID:34580980 doi:https://dx.doi.org/10.15252/embr.202152675

[1]

[2]

@@ Line 3: / Line 3: @@
 <StructureSection load='7l4j' size='340' side='right'caption='[[7l4j]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7l4j]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7L4J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L4J FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7l4j]] 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=7L4J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L4J FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 2.451&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PPM1H, ARHCL1, KIAA1157, URCC2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Phosphoprotein_phosphatase Phosphoprotein phosphatase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.16 3.1.3.16] </span></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=7l4j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l4j OCA], [https://pdbe.org/7l4j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l4j RCSB], [https://www.ebi.ac.uk/pdbsum/7l4j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l4j ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/PPM1H_HUMAN PPM1H_HUMAN]] Dephosphorylates CDKN1B at 'Thr-187', thus removing a signal for proteasomal degradation.<ref>PMID:22586611</ref>
+[https://www.uniprot.org/uniprot/PPM1H_HUMAN PPM1H_HUMAN] Dephosphorylates CDKN1B at 'Thr-187', thus removing a signal for proteasomal degradation.<ref>PMID:22586611</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Phosphoprotein phosphatase]]
+[[Category: Khan AR]]
-[[Category: Khan, A R]]
+[[Category: Waschbusch D]]
-[[Category: Waschbusch, D]]
-[[Category: Hydrolase]]
-[[Category: Lrrk2 kinase]]
-[[Category: Membrane trafficking]]
-[[Category: Rab gtpase]]

7l4j: Difference between revisions

Latest revision as of 15:37, 18 October 2023

Crystal structure of WT PPM1H phosphatase

Structural highlights

Function

Publication Abstract from PubMed

References

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