| Structural highlights
4gtx is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Related: | 4gtw, 4gty, 4gtz |
| Gene: | Enpp2, Npps2, Pdnp2, Enpp1, mCG_9001 (LK3 transgenic mice) |
| Activity: | Alkylglycerophosphoethanolamine phosphodiesterase, with EC number 3.1.4.39 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[ENPP2_MOUSE] Note=May contribute to obesity.
Function
[ENPP2_MOUSE] Hydrolyzes lysophospholipids to produce lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Also can act on sphingosylphosphphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility. Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP. Involved in several motility-related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development. Tumor cell motility-stimulating factor.[1] [2] [3]
Publication Abstract from PubMed
Enpp1 is a membrane-bound glycoprotein that regulates bone mineralization by hydrolyzing extracellular nucleotide triphosphates to produce pyrophosphate. Enpp1 dysfunction causes human diseases characterized by ectopic calcification. Enpp1 also inhibits insulin signaling, and an Enpp1 polymorphism is associated with insulin resistance. However, the precise mechanism by which Enpp1 functions in these cellular processes remains elusive. Here, we report the crystal structures of the extracellular region of mouse Enpp1 in complex with four different nucleotide monophosphates, at resolutions of 2.7-3.2 A. The nucleotides are accommodated in a pocket formed by an insertion loop in the catalytic domain, explaining the preference of Enpp1 for an ATP substrate. Structural mapping of disease-associated mutations indicated the functional importance of the interdomain interactions. A structural comparison of Enpp1 with Enpp2, a lysophospholipase D, revealed marked differences in the domain arrangements and active-site architectures. Notably, the Enpp1 mutant lacking the insertion loop lost the nucleotide-hydrolyzing activity but instead gained the lysophospholipid-hydrolyzing activity of Enpp2. Our findings provide structural insights into how the Enpp family proteins evolved to exert their diverse cellular functions.
Crystal structure of Enpp1, an extracellular glycoprotein involved in bone mineralization and insulin signaling.,Kato K, Nishimasu H, Okudaira S, Mihara E, Ishitani R, Takagi J, Aoki J, Nureki O Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16876-81. doi:, 10.1073/pnas.1208017109. Epub 2012 Oct 1. PMID:23027977[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Boucher J, Quilliot D, Praderes JP, Simon MF, Gres S, Guigne C, Prevot D, Ferry G, Boutin JA, Carpene C, Valet P, Saulnier-Blache JS. Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression. Diabetologia. 2005 Mar;48(3):569-77. Epub 2005 Feb 8. PMID:15700135 doi:10.1007/s00125-004-1660-8
- ↑ Pradere JP, Tarnus E, Gres S, Valet P, Saulnier-Blache JS. Secretion and lysophospholipase D activity of autotaxin by adipocytes are controlled by N-glycosylation and signal peptidase. Biochim Biophys Acta. 2007 Jan;1771(1):93-102. Epub 2006 Dec 6. PMID:17208043 doi:10.1016/j.bbalip.2006.11.010
- ↑ Nishimasu H, Okudaira S, Hama K, Mihara E, Dohmae N, Inoue A, Ishitani R, Takagi J, Aoki J, Nureki O. Crystal structure of autotaxin and insight into GPCR activation by lipid mediators. Nat Struct Mol Biol. 2011 Feb;18(2):205-12. doi: 10.1038/nsmb.1998. Epub 2011 Jan, 16. PMID:21240269 doi:10.1038/nsmb.1998
- ↑ Kato K, Nishimasu H, Okudaira S, Mihara E, Ishitani R, Takagi J, Aoki J, Nureki O. Crystal structure of Enpp1, an extracellular glycoprotein involved in bone mineralization and insulin signaling. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16876-81. doi:, 10.1073/pnas.1208017109. Epub 2012 Oct 1. PMID:23027977 doi:http://dx.doi.org/10.1073/pnas.1208017109
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