4p0c: Difference between revisions

Revision as of 17:56, 25 December 2014

Crystal Structure of NHERF2 PDZ1 Domain in Complex with LPA2

Structural highlights

4p0c is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	CL, SCN
Resources:	FirstGlance, OCA, RCSB, PDBsum

Function

[NHRF2_HUMAN] Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May also act as scaffold protein in the nucleus.^[1] ^[2]

Publication Abstract from PubMed

The formation of CFTR-NHERF2-LPA2 macromolecular complex in airway epithelia regulates CFTR channel function and plays an important role in compartmentalized cAMP signaling. We previously have shown that disruption of the PDZ-mediated NHERF2-LPA2 interaction abolishes the LPA inhibitory effect and augments CFTR Cl(-) channel activity in vitro and in vivo. Here we report the first crystal structure of the NHERF2 PDZ1 domain in complex with the C-terminal LPA2 sequence. The structure reveals that the PDZ1-LPA2 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four LPA2 residues contributing to specific interactions. Comparison of the PDZ1-LPA2 structure to the structure of PDZ1 in complex with a different peptide provides insights into the diverse nature of PDZ1 substrate recognition and suggests that the conformational flexibility in the ligand binding pocket is involved in determining the broad substrate specificity of PDZ1. In addition, the structure reveals a small surface pocket adjacent to the ligand-binding site, which may have therapeutic implications. This study provides an understanding of the structural basis for the PDZ-mediated NHERF2-LPA2 interaction that could prove valuable in selective drug design against CFTR-related human diseases.

Structural insights into PDZ-mediated interaction of NHERF2 and LPA(2), a cellular event implicated in CFTR channel regulation.,Holcomb J, Jiang Y, Lu G, Trescott L, Brunzelle J, Sirinupong N, Li C, Naren AP, Yang Z Biochem Biophys Res Commun. 2014 Mar 28;446(1):399-403. doi:, 10.1016/j.bbrc.2014.02.128. Epub 2014 Mar 12. PMID:24613836^[3]

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

References

↑ Yun CH, Oh S, Zizak M, Steplock D, Tsao S, Tse CM, Weinman EJ, Donowitz M. cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3010-5. PMID:9096337
↑ Zizak M, Lamprecht G, Steplock D, Tariq N, Shenolikar S, Donowitz M, Yun CH, Weinman EJ. cAMP-induced phosphorylation and inhibition of Na(+)/H(+) exchanger 3 (NHE3) are dependent on the presence but not the phosphorylation of NHE regulatory factor. J Biol Chem. 1999 Aug 27;274(35):24753-8. PMID:10455146
↑ Holcomb J, Jiang Y, Lu G, Trescott L, Brunzelle J, Sirinupong N, Li C, Naren AP, Yang Z. Structural insights into PDZ-mediated interaction of NHERF2 and LPA(2), a cellular event implicated in CFTR channel regulation. Biochem Biophys Res Commun. 2014 Mar 28;446(1):399-403. doi:, 10.1016/j.bbrc.2014.02.128. Epub 2014 Mar 12. PMID:24613836 doi:https://dx.doi.org/10.1016/j.bbrc.2014.02.128

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OCA

[1] Yun CH, Oh S, Zizak M, Steplock D, Tsao S, Tse CM, Weinman EJ, Donowitz M. cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3010-5. PMID:9096337

[2] Zizak M, Lamprecht G, Steplock D, Tariq N, Shenolikar S, Donowitz M, Yun CH, Weinman EJ. cAMP-induced phosphorylation and inhibition of Na(+)/H(+) exchanger 3 (NHE3) are dependent on the presence but not the phosphorylation of NHE regulatory factor. J Biol Chem. 1999 Aug 27;274(35):24753-8. PMID:10455146

[3] Holcomb J, Jiang Y, Lu G, Trescott L, Brunzelle J, Sirinupong N, Li C, Naren AP, Yang Z. Structural insights into PDZ-mediated interaction of NHERF2 and LPA(2), a cellular event implicated in CFTR channel regulation. Biochem Biophys Res Commun. 2014 Mar 28;446(1):399-403. doi:, 10.1016/j.bbrc.2014.02.128. Epub 2014 Mar 12. PMID:24613836 doi:https://dx.doi.org/10.1016/j.bbrc.2014.02.128

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4p0c]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4P0C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4P0C FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene></td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4p0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4p0c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4p0c RCSB], [http://www.ebi.ac.uk/pdbsum/4p0c PDBsum]</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=4p0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4p0c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4p0c RCSB], [http://www.ebi.ac.uk/pdbsum/4p0c PDBsum]</span></td></tr>
-<table>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/NHRF2_HUMAN NHRF2_HUMAN]] Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May also act as scaffold protein in the nucleus.<ref>PMID:9096337</ref> <ref>PMID:10455146</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 18: / Line 20: @@
 __TOC__
 </StructureSection>
-[[Category: Brunzelle, J.]]
+[[Category: Brunzelle, J]]
-[[Category: Holcomb, J.]]
+[[Category: Holcomb, J]]
-[[Category: Jiang, Y.]]
+[[Category: Jiang, Y]]
-[[Category: Li, C.]]
+[[Category: Li, C]]
-[[Category: Lu, G.]]
+[[Category: Lu, G]]
-[[Category: Naren, A.]]
+[[Category: Naren, A]]
-[[Category: Sirinupong, N.]]
+[[Category: Sirinupong, N]]
-[[Category: Trescott, L.]]
+[[Category: Trescott, L]]
-[[Category: Yang, Z.]]
+[[Category: Yang, Z]]
 [[Category: Pdz]]
 [[Category: Protein binding]]
 [[Category: Protein-protein interaction]]

4p0c: Difference between revisions

Revision as of 17:56, 25 December 2014

Crystal Structure of NHERF2 PDZ1 Domain in Complex with LPA2

Structural highlights

Function

Publication Abstract from PubMed

References

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