Crystal Structure of the Nucleotide-metabolizing Enzyme NTPDase4

Overview

Journal Protein Sci

Specialty Biochemistry

Date 2020 Aug 9

PMID 32767432

Citations 4

Authors

Alexei Gorelik

Jonathan M Labriola

Katalin Illes

Bhushan Nagar

Affiliations

Soon will be listed here.

Abstract

The ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) are a family of enzymes found on the cell surface and in the lumen of certain organelles, that are major regulators of purinergic signaling. Their intracellular roles, however, have not been clearly defined. NTPDase4 (UDPase, ENTPD4) is a Golgi protein potentially involved in nucleotide recycling as part of protein glycosylation, and is also found in lysosomes, where its purpose is unknown. To further our understanding of NTPDase4 function, we determined its crystal structure. The enzyme adopts a wide open, inactive conformation. Differences in the nucleotide-binding site relative to its homologs could account for its substrate selectivity. The putative membrane-interacting loop of cell-surface NTPDases is drastically altered in NTPDase4, potentially affecting its interdomain dynamics at the Golgi membrane.

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References

Hirschberg C, Robbins P, Abeijon C . Transporters of nucleotide sugars, ATP, and nucleotide sulfate in the endoplasmic reticulum and Golgi apparatus. Annu Rev Biochem. 1998; 67:49-69. DOI: 10.1146/annurev.biochem.67.1.49. View

Al-Rashida M, Iqbal J . Therapeutic potentials of ecto-nucleoside triphosphate diphosphohydrolase, ecto-nucleotide pyrophosphatase/phosphodiesterase, ecto-5'-nucleotidase, and alkaline phosphatase inhibitors. Med Res Rev. 2013; 34(4):703-43. DOI: 10.1002/med.21302. View

Zebisch M, Krauss M, Schafer P, Strater N . Structures of Legionella pneumophila NTPDase1 in complex with polyoxometallates. Acta Crystallogr D Biol Crystallogr. 2014; 70(Pt 4):1147-54. DOI: 10.1107/S1399004714001916. View

Otwinowski Z, Minor W . Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 1997; 276:307-26. DOI: 10.1016/S0076-6879(97)76066-X. View

Knowles A . The single NTPase gene of Drosophila melanogaster encodes an intracellular nucleoside triphosphate diphosphohydrolase 6 (NTPDase6). Arch Biochem Biophys. 2009; 484(1):70-9. DOI: 10.1016/j.abb.2009.01.005. View

Grinthal A, Guidotti G . CD39, NTPDase 1, is attached to the plasma membrane by two transmembrane domains. Why?. Purinergic Signal. 2008; 2(2):391-8. PMC: 2254477. DOI: 10.1007/s11302-005-5907-8. View

Wang T, Guidotti G . Golgi localization and functional expression of human uridine diphosphatase. J Biol Chem. 1998; 273(18):11392-9. DOI: 10.1074/jbc.273.18.11392. View

Emsley P, Lohkamp B, Scott W, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 4):486-501. PMC: 2852313. DOI: 10.1107/S0907444910007493. View

Adams P, Afonine P, Bunkoczi G, Chen V, Davis I, Echols N . PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 2):213-21. PMC: 2815670. DOI: 10.1107/S0907444909052925. View

10.

Zebisch M, Krauss M, Schafer P, Lauble P, Strater N . Crystallographic snapshots along the reaction pathway of nucleoside triphosphate diphosphohydrolases. Structure. 2013; 21(8):1460-75. DOI: 10.1016/j.str.2013.05.016. View

11.

Krug U, Totzauer R, Strater N . The crystal structure of Toxoplasma gondii nucleoside triphosphate diphosphohydrolase 1 represents a conformational intermediate in the reductive activation mechanism of the tetrameric enzyme. Proteins. 2013; 81(7):1271-6. DOI: 10.1002/prot.24288. View

12.

Biederbick A, Rosser R, Storre J, Elsasser H . The VSFASSQQ motif confers calcium sensitivity to the intracellular apyrase LALP70. BMC Biochem. 2004; 5:8. PMC: 443525. DOI: 10.1186/1471-2091-5-8. View

13.

Krug U, Totzauer R, Zebisch M, Strater N . The ATP/ADP substrate specificity switch between Toxoplasma gondii NTPDase1 and NTPDase3 is caused by an altered mode of binding of the substrate base. Chembiochem. 2013; 14(17):2292-300. DOI: 10.1002/cbic.201300441. View

14.

Biederbick A, Rose S, Elsasser H . A human intracellular apyrase-like protein, LALP70, localizes to lysosomal/autophagic vacuoles. J Cell Sci. 1999; 112 ( Pt 15):2473-84. DOI: 10.1242/jcs.112.15.2473. View

15.

Zebisch M, Krauss M, Schafer P, Strater N . Crystallographic evidence for a domain motion in rat nucleoside triphosphate diphosphohydrolase (NTPDase) 1. J Mol Biol. 2011; 415(2):288-306. DOI: 10.1016/j.jmb.2011.10.050. View

16.

Zimmermann H, Zebisch M, Strater N . Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal. 2012; 8(3):437-502. PMC: 3360096. DOI: 10.1007/s11302-012-9309-4. View

17.

Vivian J, Riedmaier P, Ge H, Le Nours J, Sansom F, Wilce M . Crystal structure of a Legionella pneumophila ecto -triphosphate diphosphohydrolase, a structural and functional homolog of the eukaryotic NTPDases. Structure. 2010; 18(2):228-38. DOI: 10.1016/j.str.2009.11.014. View

18.

Krug U, Zebisch M, Krauss M, Strater N . Structural insight into activation mechanism of Toxoplasma gondii nucleoside triphosphate diphosphohydrolases by disulfide reduction. J Biol Chem. 2011; 287(5):3051-66. PMC: 3270962. DOI: 10.1074/jbc.M111.294348. View

19.

Fang M, Shen Z, Huang S, Zhao L, Chen S, Mak T . The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell. 2010; 143(5):711-24. DOI: 10.1016/j.cell.2010.10.010. View

20.

Giuliani A, Sarti A, Di Virgilio F . Extracellular nucleotides and nucleosides as signalling molecules. Immunol Lett. 2018; 205:16-24. DOI: 10.1016/j.imlet.2018.11.006. View