title: Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulate signaling.
abstract: The T-cell receptor (TCR) consists of a TCRαβ heterodimer, a TCRζ homodimer, and CD3γε and CD3δε heterodimers. The precise mechanism of T-cell triggering following TCR ligand engagement remains elusive. Previous studies reported that the cytoplasmic tail of CD3ε binds to the plasma membrane through a basic residue-rich stretch (BRS) and proposed that dissociation from the membrane is required for phosphorylation thereof. In this report we show that BRS motifs within the cytoplasmic tail of TCRζ mediate association with the plasma membrane and that TCR engagement results in TCRζ dissociation from the membrane. This dissociation requires phosphorylation of the TCRζ immunoreceptor tyrosine-based activation motifs by lymphocyte cell-specificprotein tyrosine kinase (Lck) but not ζ-chain-associated protein kinase 70 binding. Mutations of the TCRζ BRS motifs that disrupt this membrane association attenuate proximal and distal responses induced by TCR engagement. These mutations appear to alter the localization of TCRζ with respect to Lck as well as the mobility of the TCR complex. This study reveals that tyrosine phosphorylation of the TCRζ cytoplasmic domain regulates its association with the plasma membrane and highlights the functional importance of TCRζ BRS motifs.
authors.affiliation: The Sir William Dunn School of Pathology,  University of Oxford, Oxford OX1 3RE,  United Kingdom.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Shaun-Paul
authors.initials: SP
authors.lastname: Cordoba
authors.forename: Omer
authors.initials: O
authors.lastname: Dushek
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D047468:Immunoprecipitation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D014443:Tyrosine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
references.citation: Cell. 2002 Jun 28;109(7):901-12
references.pmid: 12110186
references.citation: Biochem Biophys Res Commun. 2009 Nov 13;389(2):388-93
references.pmid: 19733547
references.citation: Immunity. 1996 Jul;5(1):53-61
references.pmid: 8758894
references.citation: Cell. 2008 Nov 14;135(4):594-6
references.pmid: 19013269
references.citation: Nat Rev Immunol. 2007 Nov;7(11):841-50
references.pmid: 17960150
references.citation: Nat Rev Immunol. 2011 Jan;11(1):47-55
references.pmid: 21127503
references.citation: Nat Immunol. 2008 May;9(5):522-32
references.pmid: 18408722
references.citation: Methods. 2001 Jul;24(3):289-96
references.pmid: 11403577
references.citation: Immunity. 2010 Jul 23;33(1):60-70
references.pmid: 20637659
references.citation: Cell. 2010 Sep 3;142(5):669-71
references.pmid: 20813252
references.citation: J Immunol. 2009 Jul 15;183(2):1055-64
references.pmid: 19542373
references.citation: J Biol Chem. 1996 Jan 12;271(2):695-701
references.pmid: 8557675
references.citation: Cell. 2008 Nov 14;135(4):702-13
references.pmid: 19013279
references.citation: Cell. 1988 Jan 15;52(1):85-95
references.pmid: 3278811
references.citation: PLoS One. 2008 Mar 05;3(3):e1747
references.pmid: 18320063
references.citation: J Exp Med. 2005 Feb 21;201(4):517-22
references.pmid: 15728235
references.citation: Nat Struct Biol. 2000 Nov;7(11):1023-6
references.pmid: 11062556
references.citation: J Immunol. 2011 Jun 15;186(12):6839-47
references.pmid: 21543646
references.citation: Biochemistry. 2006 Dec 26;45(51):15731-9
references.pmid: 17176095
references.citation: J Immunol. 2005 Jul 1;175(1):270-5
references.pmid: 15972658
references.citation: Annu Rev Immunol. 2010;28:79-105
references.pmid: 19968559
references.citation: Immunity. 2010 Jun 25;32(6):766-77
references.pmid: 20541955
references.citation: Annu Rev Immunol. 2006;24:419-66
references.pmid: 16551255
references.citation: Cell. 2010 Sep 3;142(5):668-9
references.pmid: 20813251
references.citation: Cell. 1992 Jan 10;68(1):83-95
references.pmid: 1531041