title: NMR structure of integrin α4 cytosolic tail and its interactions with paxillin.
abstract: BACKGROUND
  Integrins are a group of transmembrane signaling proteins that are important in biological processes such as cell adhesion, proliferation and migration. Integrins are α/β hetero-dimers and there are 24 different integrins formed by specific combinations of 18 α and 8 β subunits in humans. Generally, each of these subunits has a large extracellular domain, a single pass transmembrane segment and a cytosolic tail (CT). CTs of integrins are important in bidirectional signal transduction and they associate with a large number of intracellular proteins.
  
  
  RESULTS
  Using NMR spectroscopy, we determined the 3-D structure of the full-length α4 CT (Lys968-Asp999) and characterize its interactions with the adaptor protein paxillin. The α4 CT assumes an overall helical structure with a kink in its membrane proximal region. Residues Gln981-Asn997 formed a continuous helical conformation that may be sustained by potential ionic and/or hydrogen bond interactions and packing of aromatic-aliphatic side-chains. ¹⁵N-¹H HSQC NMR experiments reveal interactions of the α4 CT C-terminal region with a fragment of paxillin (residues G139-K277) that encompassed LD2-LD4 repeats. Residues of these LD repeats including their adjoining linkers showed α4 CT binding-induced chemical shift changes. Furthermore, NMR studies using LD-containing peptides showed predominant interactions between LD3 and LD4 of paxillin and α4 CT. Docked structures of the α4 CT with these LD repeats suggest possible polar and/or salt-bridge and non-polar packing interactions.
  
  
  CONCLUSIONS
  The current study provides molecular insights into the structural diversity of α CTs of integrins and interactions of integrin α4 CT with the adaptor protein paxillin.
authors: School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors: Geok-Lin
authors: GL
authors: Chua
authors: Alok Tanala
authors: AT
authors: Patra
authors: Suet-Mien
authors: SM
authors: Tan
authors: Surajit
authors: S
authors: Bhattacharjya
mesh_terms: D000595:Amino Acid Sequence; D039441:Integrin alpha4 / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D051419:Paxillin / Q000737:chemistry* / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D051419:Paxillin; D010446:Peptide Fragments; D039441:Integrin alpha4
references: Curr Opin Cell Biol. 2007 Feb;19(1):43-50
references: 17184985
references: J Biol Chem. 2002 Jun 7;277(23):20887-94
references: 11919182
references: J Biol Chem. 2001 Nov 2;276(44):40903-9
references: 11533025
references: J Immunol. 2000 Jan 15;164(2):746-53
references: 10623819
references: J Biol Chem. 1999 Jul 16;274(29):20550-60
references: 10400685
references: Mol Cell Biol. 1996 Nov;16(11):6408-18
references: 8887669
references: Mol Biol Cell. 1995 Jun;6(6):661-74
references: 7579686
references: PLoS One. 2012;7(7):e41924
references: 22844534
references: J Cell Biol. 2003 Aug 18;162(4):731-41
references: 12913113
references: J Biol Chem. 2000 Jul 28;275(30):22736-42
references: 10781578
references: Biosci Rep. 2012 Jun;32(3):241-69
references: 22458844
references: Structure. 2003 Oct;11(10):1207-17
references: 14527389
references: Exp Mol Med. 2006 Jun 30;38(3):191-5
references: 16819276
references: J Biol Chem. 2001 Oct 5;276(40):37086-92
references: 11477105
references: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1450-5
references: 10677482
references: Nat Cell Biol. 2000 Dec;2(12):E231-6
references: 11146675
references: Cell. 1990 Feb 23;60(4):577-84
references: 1689216
references: J Biol Chem. 2012 Sep 21;287(39):32566-77
references: 22869380
references: J Cell Sci. 2009 Jan 15;122(Pt 2):179-86
references: 19118210
references: Mol Cell Biol. 2002 Apr;22(8):2751-60
references: 11909967
references: Am J Gastroenterol. 2003 Nov;98(11):2372-82
references: 14638336
references: J Mol Biol. 1997 Oct 17;273(1):283-98
references: 9367762
references: Mol Biol Cell. 2001 Oct;12(10):3214-25
references: 11598204
references: Exp Cell Res. 2000 Aug 1;258(2):342-51
references: 10896785
references: J Cell Biol. 1995 Mar;128(6):1243-53
references: 7534768
references: Blood. 2000 Jul 15;96(2):506-13
references: 10887112
references: J Biol Chem. 2009 Feb 6;284(6):3873-84
references: 19073598
references: Development. 1995 Feb;121(2):549-60
references: 7539359
references: Biochemistry. 2002 Jan 8;41(1):1-7
references: 11771996
references: Cell. 2002 Sep 20;110(6):673-87
references: 12297042
references: J Biol Chem. 1991 Feb 25;266(6):3579-85
references: 1750929
references: Curr Opin Cell Biol. 2012 Oct;24(5):592-9
references: 22857903
references: Cell. 1993 Jul 16;74(1):185-95
references: 7687523
references: Nat Struct Biol. 2002 Feb;9(2):101-6
references: 11799401
references: Cell. 2006 Dec 1;127(5):1015-26
references: 17129785
references: J Biol Chem. 2008 Jul 25;283(30):21113-9
references: 18508764
references: Cold Spring Harb Perspect Biol. 2011 Sep 01;3(9):a005074
references: 21885598
references: Nature. 1999 Dec 9;402(6762):676-81
references: 10604475
references: Cell. 1995 Feb 10;80(3):413-22
references: 7532110
references: J Clin Invest. 2006 Mar;116(3):715-23
references: 16470243
references: J Cell Sci. 2009 Jan 15;122(Pt 2):171-7
references: 19118209
references: Am J Pathol. 1997 Jul;151(1):97-110
references: 9212736
references: Cell. 1996 Jun 28;85(7):997-1008
references: 8674127
references: J Biol Chem. 2010 Mar 26;285(13):9462-9469
references: 20097761
references: Neurology. 2005 Apr 26;64(8):1336-42
references: 15851719
references: J Biol Chem. 2011 Dec 23;286(51):43842-43854
references: 22052909
references: J Biol Chem. 1998 Mar 13;273(11):6474-81
references: 9497381
references: Nat Cell Biol. 2005 Apr;7(4):343-52
references: 15793570