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(PX) Domain Protein Grd19p Complexed to Phosphatidylinositol-3-Phosphate

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(PX) Domain Protein Grd19p Complexed to Phosphatidylinositol-3-Phosphate Crystal Structure of the Yeast Phox Homology (PX) Domain Protein Grd19p Complexed to Phosphatidylinositol-3-phosphate Cong-Zhao Zhou, Ines Li de la Sierra-Gallay, Sophie Quevillon-Cheruel, Bruno Collinet, Philippe Minard, Karine Blondeau, Gilles Henckes, Robert Aufrère, Nicolas Leulliot, Marc Graille, et al. To cite this version: Cong-Zhao Zhou, Ines Li de la Sierra-Gallay, Sophie Quevillon-Cheruel, Bruno Collinet, Philippe Minard, et al.. Crystal Structure of the Yeast Phox Homology (PX) Domain Protein Grd19p Com- plexed to Phosphatidylinositol-3-phosphate. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2003, 278 (50), pp.50371 - 50376. 10.1074/jbc.m304392200. hal-03299367 HAL Id: hal-03299367 https://hal.archives-ouvertes.fr/hal-03299367 Submitted on 26 Jul 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 278, No. 50, Issue of December 12, pp. 50371–50376, 2003 © 2003 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. Crystal Structure of the Yeast Phox Homology (PX) Domain Protein Grd19p Complexed to Phosphatidylinositol-3-phosphate* Received for publication, April 28, 2003, and in revised form, September 25, 2003 Published, JBC Papers in Press, September 26, 2003, DOI 10.1074/jbc.M304392200 Cong-Zhao Zhou‡, Ines Li de La Sierra-Gallay§, Sophie Quevillon-Cheruel‡, Bruno Collinet‡, Philippe Minard‡, Karine Blondeau¶, Gilles Henckes¶, Robert Aufre`re¶, Nicolas Leulliot‡, Marc Graille§, Isabelle Sorel‡, Philippe Savarin§, Franc¸oise de la Torre§, Anne Poupon§, Joe¨l Janin§, and Herman van Tilbeurgh‡ʈ From the ‡Institut de Biochimie et de Biophysique Mole´culaire et Cellulaire (CNRS-Unite´ Mixte de Recherche 8619), Universite´ Paris-Sud, Baˆt. 430, 91405 Orsay, France, the §Laboratoire d’Enzymologie et Biochimie Structurales (CNRS- Unite´ Propre de Recherche 9063), Baˆt. 34, 1 Av. de la Terrasse, 91198 Gif sur Yvette, France, and the ¶Institut de Ge´ne´tique et Microbiologie (CNRS-Unite´ Mixte de Recherche 8621), Universite´ Paris-Sud, Baˆt. 360, 91405 Orsay, France Phox homology (PX) domains have been recently iden- A number of PI-binding motifs have now been characterized tified in a number of different proteins and are involved such as the FYVE domain (2), the pleckstrin homology domain in various cellular functions such as vacuolar targeting (3), the epsin N-terminal homology domain (4), and the Phox and membrane protein trafficking. It was shown that homology (PX) domain (5). The PX domain was first identified these modules of about 130 amino acids specifically as a motif of about 130 amino acids present in the p40phox and binding to phosphoinositides and that this interaction is p47phox subunits of the neutrophil NADPH oxidase superoxide- crucial for their cellular function. The yeast genome generating complex. The PX domain was afterward recognized contains 17 PX domain proteins. One of these, Grd19p, is in a vast number of other proteins covering a wide palette of involved in the localization of the late Golgi membrane molecular functions: cell signaling pathways (phospholipases proteins DPAP A and Kex2p. Grd19p consists of the PX D, phosphatidylinositol 3-kinase), vesicular trafficking and domain with 30 extra residues at the N-terminal and is yeast morphology (human sorting nexins; yeast Vps5p, Vps17p, homologous to the functionally characterized human Vam7p, and Mvp1p) and control of yeast budding and cell sorting nexin protein SNX3. We determined the 2.0 Å crystal structure of Grd19p in the free form and in com- polarity (Bem1p and Bem3p). The PX domain can be present alone or in combination with plex with D-myo-phosphatidylinositol 3-phosphate other functional domains (6). Three broad subclasses of PX (diC4PtdIns(3)P), representing the first case of both free and ligand-bound conformations of the same PX module. containing proteins can be distinguished. The first subclass The ligand occupies a well defined positively charged contains small proteins that essentially consist of the PX do- binding pocket at the interface between the ␤-sheet and main (sorting nexin 3 (SNX3), SNX10, SNX12, SNX23, SNX24, ␣-helical parts of the molecule. The structure of the free SNX26, and yeast Grd19p). PX domains in the second subclass and bound protein are globally similar but show some contain extra sequences, such as coiled-coil regions that are significant differences in a region containing a polypro- involved in complex formation with other partners (SNX1, line peptide and a putative membrane attachment site. SNX2, Pps5, SNX4, SNX5, and SNX6). The third subclass encompasses PX proteins that contain additional well charac- terized domains: SH3 motifs are present in SNX9, SNX18, Phosphatidylinositol (PI)1 and its phosphorylated deriva- SNX28, p40phox, p47phox, FISH, Bem1p and Scd2p, but many tives regulate many biological processes, including cell prolif- more domain combinations exist (for a recent review see Ref. 7). eration, cell survival, differentiation, signal transduction, cy- Sorting nexins are found in a variety of organisms as regu- toskeleton organization, and membrane trafficking (reviewed lators of cellular protein trafficking that have the presence of in Ref. 1). Various chemical species can be generated by single, the PX domain in common (7–9). The dynamic vessel transport double, or triple phosphorylations at the inositol hydroxy processes at the late Golgi compartment of yeast (trans-Golgi groups at positions 3, 4, and 5. Their synthesis and cellular network) require dedicated mechanisms for correct localization concentrations are regulated by specific lipid kinases and phos- of resident membrane proteins. Recently a new gene, GRD19, phatases. One of the major mechanisms by which PIs regulate was identified to be involved in the localization of late Golgi cellular processes is by their capacity to serve as membrane membrane proteins. It was concluded that Grd19p is a compo- signals to affect intracellular localizations of effector proteins. nent of the retrieval machinery that functions by direct inter- action with the cytosolic tails of certain TGN membrane pro- * This work is supported by grants from the Ministe`re de la Recher- teins during the sorting/budding process at the prevacuolar che et de la Technologie (Programme Ge´nopoles) and the Association compartment (10). The mammalian orthologue of Grd19p, pour la Recherche contre le Cancer (to M. G.). The costs of publication SNX3, was shown to associate with early endosomes through a of this article were defrayed in part by the payment of page charges. PX domain-mediated interaction with phosphatidylinosytol-3- This article must therefore be hereby marked “advertisement”inac- cordance with 18 U.S.C. Section 1734 solely to indicate this fact. phosphate (11). Overexpression of this protein alters/delays ʈ To whom correspondence should be addressed. Tel.: 33-1-69-82-34- transport to the lysosome. 91; Fax: 33-1-69-82-31-29; E-mail: [email protected]. The phosphoinositode binding of all yeast PX domains was 1 The abbreviations used are: PI, phosphatidylinositol; PtdIns(3)P, recently experimentally analyzed, and they all bind PtdIns(3)P phosphatidylinositol 3-phosphate; DiC PtdIns(3)P, D-myo-phosphatidyl- 4 with high affinity. The glutathione S-transferase SNX3/ inositol 3-phosphate; PX, Phox homology; SH, Src homology; SNX, sorting nexin; IPTG, isopropyl-1-thio-␤-D-galactopyranoside; RMS, root Grd19p fusion protein in particular was shown to bind with an ␮ mean square. apparent Kd between 0.15 and 0.5 M (12). This paper is available on line at http://www.jbc.org 50371 50372 Crystal Structure of Grd19p Complexed to PI-3-phosphate TABLE I Data collection and refinement statistics Complex Native Edge Peak Remote Wavelength (Å) 0.984 0.9797 0.9803 0.98 0.9825 f Ј,fЈЈ Ϫ21.09, 7.93 Ϫ12.88, 17.04 Ϫ9.74, 0.65 Unit-cell parameters/Spcgrp P1 P 61 22 a, b, c (Å) 31.43, 55.76, 64.75 55.73, 55.73, 187.51 ␣, ␤, ␥ (°) 110.75, 97.35, 99.49 90, 90, 120 Resolution (Å) 25.08–2.28 25–2.03 25–2.33 25–2.33 25–2.33 Total number of reflections 65105 60571 67536 67464 40121 Number of unique reflections 11970 17289 7654 7671 7503 Multiplicity 3.8 5.1 8.8 8.8 5.3 a,b Rmerge 0.047 (0.156) 0.065 (0.296) 0.057 (0.254) 0.057 (0.2) 0.032 (0.155) I/␴(I)a 25.1 (3.2) 13.6 (2.5) 21.2 (3.4) 26.6 (5.0) 27.0 (5.8) Overall completeness (%)a 95.97 (77.31) 99.7 (98.1) 96.9 (96.1) 97.1 (96.3) 95.0 (87.4) Refinement Resolution (Å)20–2.3 20–2.03 c Rcryst/Rfree 0.222/0.256 0.217/0.247 Non-hydrogen atoms 2231 1089 Water molecules 78 63 Mean B protein/ligand/wat (Å2) 41/46/40 25.3/-/29 Root mean square deviation Bonds (Å) 0.007 0.006 Angles (°) 1.3 1.2 Ramachandran analysis Most-favored 90.4 93.2 Allowed 9.6 6.8 a Numbers in parentheses are for highest resolution sell. b ϭ⌺⌺ Ϫ͗ ͘ ⌺ ⌺ ͗ ͘ Rmerge h i|Ihi Ih |/ h iIhi, where Ihi is the ith observation of the reflection h, while Ih is the mean intensity of reflection h. c ϭ⌺࿣ Ϫ ࿣ |Rfactor Fo| |Fc /|Fo|. Rfree was calculated with a small fraction (4.8%) of randomly selected reflections.
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