title: Annular anionic lipids stabilize the integrin αIIbβ3 transmembrane complex.
abstract: Cationic membrane-proximal amino acids determine the topology of membrane proteins by interacting with anionic lipids that are restricted to the intracellular membrane leaflet. This mechanism implies that anionic lipids interfere with electrostatic interactions of membrane proteins. The integrin αIIbβ3 transmembrane (TM) complex is stabilized by a membrane-proximal αIIb(Arg(995))-β3(Asp(723)) interaction; here, we examine the influence of anionic lipids on this complex. Anionic lipids compete for αIIb(Arg(995)) contacts with β3(Asp(723)) but paradoxically do not diminish the contribution of αIIb(Arg(995))-β3(Asp(723)) to TM complex stability. Overall, anionic lipids in annular positions stabilize the αIIbβ3 TM complex by up to 0.50 ± 0.02 kcal/mol relative to zwitterionic lipids in a headgroup structure-dependent manner. Comparatively, integrin receptor activation requires TM complex destabilization of 1.5 ± 0.2 kcal/mol, revealing a sizeable influence of lipid composition on TM complex stability. We implicate changes in lipid headgroup accessibility to small molecules (physical membrane characteristics) and specific but dynamic protein-lipid contacts in this TM helix-helix stabilization. Thus, anionic lipids in ubiquitous annular positions can benefit the stability of membrane proteins while leaving membrane-proximal electrostatic interactions intact.
authors: From the Department of Biochemistry & Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 and.
authors: Thomas
authors: T
authors: Schmidt
authors: From the Department of Biochemistry & Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 and.
authors: Jae-Eun
authors: JE
authors: Suk
authors: the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors: Feng
authors: F
authors: Ye
authors: From the Department of Biochemistry & Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 and.
authors: Alan J
authors: AJ
authors: Situ
authors: From the Department of Biochemistry & Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 and.
authors: Parichita
authors: P
authors: Mazumder
authors: the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors: Mark H
authors: MH
authors: Ginsberg
authors: From the Department of Biochemistry & Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 and tulmer@usc.edu.
authors: Tobias S
authors: TS
authors: Ulmer
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010713:Phosphatidylcholines / Q000737:chemistry*; D010718:Phosphatidylserines / Q000737:chemistry*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry*; D055550:Protein Stability; D017433:Protein Structure, Secondary
chemical_list: D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C050294:1-palmitoyl-2-oleoylglycero-3-phosphoserine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: Biophysics; Integrin; Membrane Lipid; Membrane Protein; Molecular Dynamics; Nuclear Magnetic Resonance (NMR); Protein-Lipid Interaction
references: Cell. 2013 Jan 31;152(3):557-69
references: 23374350
references: Mol Cell. 2009 Apr 24;34(2):234-49
references: 19394300
references: J Magn Reson. 2004 Feb;166(2):190-201
references: 14729031
references: J Biol Chem. 1992 Sep 15;267(26):18844-51
references: 1527012
references: Anal Biochem. 1989 May 15;179(1):131-7
references: 2757186
references: Blood. 2009 May 7;113(19):4747-53
references: 19218549
references: J Biomol NMR. 2004 Jul;29(3):299-308
references: 15213428
references: Biophys J. 2004 Mar;86(3):1574-86
references: 14990484
references: J Mol Biol. 2008 May 16;378(5):976-86
references: 18405917
references: J Am Chem Soc. 2003 Dec 3;125(48):14859-66
references: 14640663
references: J Biol Chem. 1996 Mar 22;271(12):6571-4
references: 8636068
references: EMBO J. 2009 May 6;28(9):1351-61
references: 19279667
references: Cell Adh Migr. 2010 Apr-Jun;4(2):243-8
references: 20168080
references: Biophys J. 2005 Mar;88(3):1887-901
references: 15626702
references: J Am Chem Soc. 2012 Jun 6;134(22):9030-3
references: 22626249
references: J Biol Chem. 1992 Aug 5;267(22):15568-77
references: 1639797
references: Biochemistry. 2008 Apr 1;47(13):4008-16
references: 18321071
references: J Thromb Haemost. 2009 Jul;7 Suppl 1:200-5
references: 19630800
references: J Phys Chem Lett. 2012 Dec 6;3(23):3498-502
references: 26290979
references: Biochim Biophys Acta. 2008 Jul-Aug;1778(7-8):1545-75
references: 18294954
references: J Biol Chem. 2009 Apr 10;284(15):9637-41
references: 19074771
references: J Mol Biol. 2014 Oct 23;426(21):3670-80
references: 25178257
references: Nature. 1989 Oct 5;341(6241):456-8
references: 2677744
references: Biochim Biophys Acta. 2004 Nov 3;1666(1-2):62-87
references: 15519309
references: J Magn Reson B. 1995 Jul;108(1):94-8
references: 7627436
references: Anal Biochem. 2008 Feb 15;373(2):395-7
references: 17920027
references: J Mol Biol. 2006 Feb 24;356(3):600-12
references: 16384584
references: Biochemistry. 2005 Apr 19;44(15):5873-83
references: 15823046
references: J Am Chem Soc. 2004 Mar 24;126(11):3477-87
references: 15025475
references: Nature. 2010 Dec 9;468(7325):834-8
references: 21107324
references: Biophys J. 2007 Feb 15;92(4):1114-24
references: 17114222
references: J Biomol NMR. 1995 Jul;6(1):59-66
references: 22911578
references: Cell. 2002 Sep 20;110(6):673-87
references: 12297042
references: J Cell Biol. 2010 Jan 11;188(1):157-73
references: 20048261
references: Biochim Biophys Acta. 2004 Nov 3;1666(1-2):2-18
references: 15519305
references: Anal Biochem. 2000 Jan 15;277(2):260-6
references: 10625516
references: Science. 2009 Dec 18;326(5960):1668-74
references: 20019282
references: Biochim Biophys Acta. 2004 Mar 22;1636(2-3):119-28
references: 15164759
references: J Biol Chem. 2008 Jun 6;283(23):16162-8
references: 18417472
references: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references: 8744570
references: Nature. 1977 Jul 28;268(5618):358-60
references: 887167
references: J Phys Chem B. 1998 Apr 30;102(18):3586-616
references: 24889800
references: Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12366-71
references: 9356455
references: Trends Biochem Sci. 2011 Sep;36(9):493-500
references: 21855348
references: J Biol Chem. 2010 Oct 1;285(40):30779-91
references: 20643655
references: Biochemistry. 2007 Feb 27;46(8):2059-69
references: 17263563
references: Anal Biochem. 1998 Aug 1;261(2):139-48
references: 9716416
references: Structure. 2011 Oct 12;19(10):1477-84
references: 22000516
references: EMBO J. 1997 Jul 16;16(14):4261-6
references: 9250669
references: Platelets. 1996;7(4):195-205
references: 21043688
references: J Biol Chem. 1990 Mar 5;265(7):4011-9
references: 1689312
references: J Mol Biol. 2002 Oct 25;323(3):563-71
references: 12381309
references: Curr Opin Struct Biol. 2005 Aug;15(4):423-31
references: 16043343