4pqw

From Proteopedia
Jump to navigation Jump to search

Crystal Structure of Phospholipase C beta 3 in Complex with PDZ1 of NHERF1Crystal Structure of Phospholipase C beta 3 in Complex with PDZ1 of NHERF1

Structural highlights

4pqw is a 1 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 1.47Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NHRF1_HUMAN Defects in SLC9A3R1 are the cause of hypophosphatemic nephrolithiasis/osteoporosis type 2 (NPHLOP2) [MIM:612287. Hypophosphatemia results from idiopathic renal phosphate loss. It contributes to the pathogenesis of hypophosphatemic urolithiasis (formation of urinary calculi) as well to that of hypophosphatemic osteoporosis (bone demineralization).[1] [2]

Function

NHRF1_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 recycling of internalized ADRB2. Was first known to play a role in the regulation of the activity and subcellular location of SLC9A3. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May enhance Wnt signaling. May participate in HTR4 targeting to microvilli (By similarity). Involved in the regulation of phosphate reabsorption in the renal proximal tubules.[3] [4] [5] [6]

Publication Abstract from PubMed

The formation of CXCR2-NHERF1-PLCbeta3 macromolecular complex in pancreatic cancer cells regulates CXCR2 signaling activity and plays an important role in tumor proliferation and invasion. We previously have shown that disruption of the NHERF1-mediated CXCR2-PLCbeta3 interaction abolishes the CXCR2 signaling cascade and inhibits pancreatic tumor growth in vitro and in vivo. Here we report the crystal structure of the NHERF1 PDZ1 domain in complex with the C-terminal PLCbeta3 sequence. The structure reveals that the PDZ1-PLCbeta3 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four PLCbeta3 residues contributing to specific interactions. We also show that PLCbeta3 can bind both NHERF1 PDZ1 and PDZ2 in pancreatic cancer cells, consistent with the observation that the peptide binding pockets of these PDZ domains are highly structurally conserved. This study provides an understanding of the structural basis for the PDZ-mediated NHERF1-PLCbeta3 interaction that could prove valuable in selective drug design against CXCR2-related cancers.

Crystallographic analysis of NHERF1-PLCbeta3 interaction provides structural basis for CXCR2 signaling in pancreatic cancer.,Jiang Y, Wang S, Holcomb J, Trescott L, Guan X, Hou Y, Brunzelle J, Sirinupong N, Li C, Yang Z Biochem Biophys Res Commun. 2014 Mar 15. pii: S0006-291X(14)00462-8. doi:, 10.1016/j.bbrc.2014.03.028. PMID:24642259[7]

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

See Also

References

  1. ↑ Karim Z, Gerard B, Bakouh N, Alili R, Leroy C, Beck L, Silve C, Planelles G, Urena-Torres P, Grandchamp B, Friedlander G, Prie D. NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med. 2008 Sep 11;359(11):1128-35. PMID:18784102 doi:359/11/1128
  2. ↑ Courbebaisse M, Leroy C, Bakouh N, Salaun C, Beck L, Grandchamp B, Planelles G, Hall RA, Friedlander G, Prie D. A new human NHERF1 mutation decreases renal phosphate transporter NPT2a expression by a PTH-independent mechanism. PLoS One. 2012;7(4):e34764. doi: 10.1371/journal.pone.0034764. Epub 2012 Apr 10. PMID:22506049 doi:10.1371/journal.pone.0034764
  3. ↑ Murthy A, Gonzalez-Agosti C, Cordero E, Pinney D, Candia C, Solomon F, Gusella J, Ramesh V. NHE-RF, a regulatory cofactor for Na(+)-H+ exchange, is a common interactor for merlin and ERM (MERM) proteins. J Biol Chem. 1998 Jan 16;273(3):1273-6. PMID:9430655
  4. ↑ 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
  5. ↑ Cao TT, Deacon HW, Reczek D, Bretscher A, von Zastrow M. A kinase-regulated PDZ-domain interaction controls endocytic sorting of the beta2-adrenergic receptor. Nature. 1999 Sep 16;401(6750):286-90. PMID:10499588 doi:10.1038/45816
  6. ↑ Karim Z, Gerard B, Bakouh N, Alili R, Leroy C, Beck L, Silve C, Planelles G, Urena-Torres P, Grandchamp B, Friedlander G, Prie D. NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med. 2008 Sep 11;359(11):1128-35. PMID:18784102 doi:359/11/1128
  7. ↑ Jiang Y, Wang S, Holcomb J, Trescott L, Guan X, Hou Y, Brunzelle J, Sirinupong N, Li C, Yang Z. Crystallographic analysis of NHERF1-PLCbeta3 interaction provides structural basis for CXCR2 signaling in pancreatic cancer. Biochem Biophys Res Commun. 2014 Mar 15. pii: S0006-291X(14)00462-8. doi:, 10.1016/j.bbrc.2014.03.028. PMID:24642259 doi:http://dx.doi.org/10.1016/j.bbrc.2014.03.028

4pqw, resolution 1.47Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=4pqw&oldid=3878726"