title: Influences of excluded volume of molecules on signaling processes on the biomembrane.
abstract: We investigate the influences of the excluded volume of molecules on biochemical reaction processes on 2-dimensional surfaces using a model of signal transduction processes on biomembranes. We perform simulations of the 2-dimensional cell-based model, which describes the reactions and diffusion of the receptors, signaling proteins, target proteins, and crowders on the cell membrane. The signaling proteins are activated by receptors, and these activated signaling proteins activate target proteins that bind autonomously from the cytoplasm to the membrane, and unbind from the membrane if activated. If the target proteins bind frequently, the volume fraction of molecules on the membrane becomes so large that the excluded volume of the molecules for the reaction and diffusion dynamics cannot be negligible. We find that such excluded volume effects of the molecules induce non-trivial variations of the signal flow, defined as the activation frequency of target proteins, as follows. With an increase in the binding rate of target proteins, the signal flow varies by i) monotonically increasing; ii) increasing then decreasing in a bell-shaped curve; or iii) increasing, decreasing, then increasing in an S-shaped curve. We further demonstrate that the excluded volume of molecules influences the hierarchical molecular distributions throughout the reaction processes. In particular, when the system exhibits a large signal flow, the signaling proteins tend to surround the receptors to form receptor-signaling protein clusters, and the target proteins tend to become distributed around such clusters. To explain these phenomena, we analyze the stochastic model of the local motions of molecules around the receptor.
authors: Department of Mathematical and Life Sciences, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan. mfujii0123@hiroshima-u.ac.jp
authors: Masashi
authors: M
authors: Fujii
authors: Hiraku
authors: H
authors: Nishimori
authors: Akinori
authors: A
authors: Awazu
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D008954:Models, Biological; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D013269:Stochastic Processes
chemical_list: D043562:Receptors, G-Protein-Coupled
references: Biophys J. 1993 Nov;65(5):2021-40
references: 8298032
references: Methods Enzymol. 1998;295:127-49
references: 9750217
references: Biophys J. 2009 Feb 18;96(4):1333-40
references: 19217851
references: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):112-7
references: 18165319
references: Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4753-8
references: 15781864
references: Biochem Soc Trans. 2006 Nov;34(Pt 5):983-8
references: 17052242
references: Biochim Biophys Acta. 2003 Jul 30;1649(2):127-39
references: 12878031
references: Biophys J. 2003 Jan;84(1):356-66
references: 12524289
references: Biophys J. 2011 Jun 22;100(12):2991-9
references: 21689533
references: Comp Biochem Physiol B Biochem Mol Biol. 1998 Sep;121(1):19-26
references: 9972281
references: Biochem Biophys Res Commun. 2009 Jan 9;378(2):285-9
references: 19026613
references: Science. 1998 Aug 28;281(5381):1305-8
references: 9721089
references: Biophys J. 2009 Aug 19;97(4):1115-24
references: 19686659
references: Mol Syst Biol. 2005;1:2005.0008
references: 16729043
references: Annu Rev Biophys Biomol Struct. 1997;26:373-99
references: 9241424
references: J Phys Chem B. 2011 Feb 10;115(5):1289-93
references: 21175126
references: Cytokine Growth Factor Rev. 2004 Apr-Jun;15(2-3):147-56
references: 15110798
references: Microbiol Rev. 1987 Dec;51(4):396-418
references: 2893972
references: Chromosome Res. 2011 Jan;19(1):63-81
references: 21116704
references: Mol Cell Biol. 2009 Apr;29(8):2082-91
references: 19188442
references: Biophys J. 2010 Aug 4;99(3):914-23
references: 20682270
references: EMBO J. 1998 May 1;17(9):2596-606
references: 9564042
references: J Cell Sci. 2005 Aug 15;118(Pt 16):3569-72
references: 16105880
references: J Cell Sci. 2006 Mar 15;119(Pt 6):1071-9
references: 16507590
references: J Cell Biol. 2002 Jun 10;157(6):1071-81
references: 12058021
references: Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5735-40
references: 16571657
references: Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10504-6
references: 1332050
references: BMC Cell Biol. 2005 Nov 30;6:41
references: 16318625
references: Biochemistry. 2002 Mar 26;41(12):3855-60
references: 11900526
references: Annu Rev Biochem. 1987;56:615-49
references: 3113327
references: Biochem J. 2005 Dec 1;392(Pt 2):249-61
references: 16293107
references: Phys Rev E Stat Nonlin Soft Matter Phys. 2002 Nov;66(5 Pt 1):051902
references: 12513518
references: Nature. 2001 Mar 1;410(6824):37-40
references: 11242034
references: J Am Chem Soc. 2010 Apr 14;132(14):5170-5
references: 20334356
references: J Am Chem Soc. 2010 Jun 30;132(25):8690-6
references: 20521820
references: Physiol Rev. 2005 Oct;85(4):1159-204
references: 16183910
references: Trends Biochem Sci. 1993 Apr;18(4):128-31
references: 8388132
references: Chem Rev. 2001 Aug;101(8):2449-76
references: 11749383
references: Annu Rev Biophys Biomol Struct. 1993;22:27-65
references: 7688609
references: Curr Opin Struct Biol. 2001 Feb;11(1):114-9
references: 11179900
references: Anal Biochem. 2010 Feb 15;397(2):247-9
references: 19837044
references: J Biol Chem. 2001 Apr 6;276(14):10577-80
references: 11279227
references: Cell. 1982 Sep;30(2):345-7
references: 6754085
references: Atherosclerosis. 2006 May;186(1):38-53
references: 16076471
references: Nat Cell Biol. 2003 Jul;5(7):626-32
references: 12819789
references: Biophys J. 2005 May;88(5):3659-80
references: 15681644
references: Chemphyschem. 2005 Aug 12;6(8):1633-40
references: 16082665
references: Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12675-80
references: 21768338
references: Biophys J. 2006 Jun 1;90(11):3993-4009
references: 16533841
references: Biosystems. 2007 Apr;88(3):251-60
references: 17184903
references: Nature. 1998 May 7;393(6680):85-8
references: 9590695
references: FEBS Lett. 2005 Mar 21;579(8):1783-8
references: 15763552