title: Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.
abstract: Transit of proteins through the endosomal organelle following endocytosis is critical for regulating the homeostasis of cell-surface proteins and controlling signal transduction pathways. However, the mechanisms that control these membrane-transport processes are poorly understood. The Phox-homology (PX) domain-containing proteins sorting nexin (SNX) 17, SNX27, and SNX31 have emerged recently as key regulators of endosomal recycling and bind conserved Asn-Pro-Xaa-Tyr-sorting signals in transmembrane cargos via an atypical band, 4.1/ezrin/radixin/moesin (FERM) domain. Here we present the crystal structure of the SNX17 FERM domain bound to the sorting motif of the P-selectin adhesion protein, revealing both the architecture of the atypical FERM domain and the molecular basis for recognition of these essential sorting sequences. We further show that the PX-FERM proteins share a promiscuous ability to bind a wide array of putative cargo molecules, including receptor tyrosine kinases, and propose a model for their coordinated molecular interactions with membrane, cargo, and regulatory proteins.
authors: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors: Rajesh
authors: R
authors: Ghai
authors: Andrea
authors: A
authors: Bugarcic
authors: Huadong
authors: H
authors: Liu
authors: Suzanne J
authors: SJ
authors: Norwood
authors: Sune
authors: S
authors: Skeldal
authors: Elizabeth J
authors: EJ
authors: Coulson
authors: Shawn Shun-Cheng
authors: SS
authors: Li
authors: Rohan D
authors: RD
authors: Teasdale
authors: Brett M
authors: BM
authors: Collins
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D011992:Endosomes / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D021381:Protein Transport; D058305:Sorting Nexins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D058305:Sorting Nexins
references: Biochem Biophys Res Commun. 2001 Mar 9;281(4):1045-50
references: 11237770
references: EMBO J. 2005 Aug 17;24(16):2851-61
references: 16052210
references: J Biol Chem. 2008 Apr 25;283(17):11501-8
references: 18276590
references: J Cell Biol. 2010 Aug 23;190(4):565-74
references: 20733053
references: Mol Biol Cell. 2009 Jan;20(1):481-97
references: 19005208
references: Nat Rev Mol Cell Biol. 2008 Jul;9(7):574-82
references: 18523436
references: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
references: 20124702
references: Cell. 2012 Jul 20;150(2):251-63
references: 22817889
references: J Biol Chem. 2004 Dec 24;279(52):54770-82
references: 15475348
references: Int J Biochem Cell Biol. 2006;38(10):1686-99
references: 16702017
references: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008 May 1;64(Pt 5):409-12
references: 18453713
references: Structure. 2010 Oct 13;18(10):1289-99
references: 20947018
references: J Biol Chem. 2012 Jun 22;287(26):22317-27
references: 22577140
references: J Biol Chem. 1990 Feb 25;265(6):3116-23
references: 1968060
references: J Cell Biol. 2012 Apr 16;197(2):219-30
references: 22492727
references: Eur J Immunol. 2008 Feb;38(2):550-64
references: 18196517
references: Curr Opin Biotechnol. 2010 Oct;21(5):611-20
references: 20817434
references: Mol Cell Biol. 2006 Nov;26(22):8461-74
references: 16982700
references: Mol Biol Cell. 2004 Jul;15(7):3095-105
references: 15121882
references: Proc Natl Acad Sci U S A. 2012 May 1;109(18):6916-21
references: 22509010
references: Cell. 1996 May 31;85(5):695-705
references: 8646778
references: EMBO J. 2000 Sep 1;19(17):4449-62
references: 10970839
references: Biochem J. 2012 Jan 1;441(1):39-59
references: 22168438
references: Proc Natl Acad Sci U S A. 2011 May 10;108(19):7763-8
references: 21512128
references: EMBO J. 2009 Nov 18;28(22):3623-32
references: 19798053
references: EMBO J. 2002 Aug 15;21(16):4259-67
references: 12169628
references: J Biol Chem. 2008 Jun 6;283(23):15656-64
references: 18381291
references: J Mol Biol. 2005 Jan 7;345(1):1-20
references: 15567406
references: Cell. 2000 Apr 28;101(3):259-70
references: 10847681
references: Endocrinology. 1995 Aug;136(8):3437-43
references: 7543044
references: Acta Crystallogr D Biol Crystallogr. 2012 Jun;68(Pt 6):620-6
references: 22683784
references: Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5831-6
references: 21422294
references: Biochem Soc Trans. 2011 Aug;39(4):839-50
references: 21787311
references: Traffic. 2011 Dec;12(12):1759-73
references: 21920005
references: Small GTPases. 2011 Sep;2(5):259-263
references: 22292128
references: J Mol Biol. 2007 Sep 21;372(3):774-97
references: 17681537
references: Biochim Biophys Acta. 2006 Aug;1761(8):878-96
references: 16782399
references: Traffic. 2001 Feb;2(2):105-10
references: 11247301
references: Nat Cell Biol. 2011 Jun;13(6):715-21
references: 21602791
references: Annu Rev Biochem. 2003;72:395-447
references: 12651740
references: Biophys J. 2001 Jun;80(6):2946-53
references: 11371467
references: Biochim Biophys Acta. 2010 May;1803(5):553-63
references: 20226821
references: Traffic. 2010 Jun;11(6):843-55
references: 20214754
references: EMBO J. 2004 Jul 21;23(14):2777-88
references: 15229651
references: J Biol Chem. 2004 Apr 16;279(16):16237-45
references: 14739284
references: Biophys J. 2005 Aug;89(2):1237-50
references: 15923225
references: Traffic. 2012 Mar;13(3):455-67
references: 22151726
references: Nat Cell Biol. 2012 May 06;14(6):584-92
references: 22561348
references: Biochem J. 2004 Jan 15;377(Pt 2):449-57
references: 14535848
references: J Appl Crystallogr. 2009 Apr 1;42(Pt 2):342-346
references: 27630371
references: J Mol Biol. 2005 Apr 8;347(4):813-25
references: 15769472
references: EMBO Rep. 2008 Nov;9(11):1134-40
references: 18833287