The origin of allosteric functional modulation: multiple pre-existing pathways.
Although allostery draws increasing attention, not much is known about allosteric mechanisms. Here we argue that in all proteins, allosteric signals transmit through multiple, pre-existing pathways; which pathways dominate depend on protein topologies, specific binding events, covalent modifications, and cellular (environmental) conditions. Further, perturbation events at any site on the protein surface (or in the interior) will not create new pathways but only shift the pre-existing ensemble of pathways. Drugs binding at different sites or mutational events in disease shift the ensemble toward the same conformations; however, the relative populations of the different states will change. Consequently the observed functional, conformational, and dynamic effects will be different. This is the origin of allosteric functional modulation in dynamic proteins: allostery does not necessarily need to invoke conformational rearrangements to control protein activity and pre-existing pathways are always defaulted to during allostery regardless of the stimulant and perturbation site in the protein.
del Sol
Antonio
A
Bioinformatics Research Unit, Research and Development Division, Fujirebio Inc., Hachioji-shi, Tokyo, Japan.
Tsai
Chung-Jung
CJ
Ma
Buyong
B
Nussinov
Ruth
R
D000494:Allosteric Regulation; D001665:Binding Sites / Q000235:genetics; D015195:Drug Design; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D011506:Proteins
Oncogene. 2006 Jan 19;25(3):370-7
16261165
Curr Opin Struct Biol. 2003 Dec;13(6):748-57
14675554
Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6620-5
19351898
J Recept Signal Transduct Res. 2007;27(4):247-59
17885921
Protein Sci. 2008 Aug;17(8):1295-307
18560010
Curr Opin Struct Biol. 2006 Feb;16(1):102-8
16423525
Drug Discov Today. 2007 Aug;12(15-16):622-33
17706543
Proteins. 2007 May 1;67(2):385-99
17295319
Mol Cell. 2007 Apr 13;26(1):131-43
17434132
J Mol Biol. 1965 May;12:88-118
14343300
J Mol Biol. 2004 Jan 23;335(4):1105-15
14698303
Mol Syst Biol. 2007;3:110
17453049
Neuropharmacology. 2007 Jan;52(1):108-17
16914173
Nat Cell Biol. 2007 Mar;9(3):331-8
17293853
Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12461-6
15314233
Mol Biosyst. 2009 Dec;5(12):1770-8
19585003
Structure. 2007 Nov;15(11):1493-504
17997974
Science. 2009 Apr 10;324(5924):198-203
19359576
J Am Chem Soc. 2009 Mar 4;131(8):3063-8
19203263
Mol Pharmacol. 2009 May;75(5):1240-7
19255243
Nat Struct Mol Biol. 2006 Sep;13(9):831-8
16906160
Science. 2001 Mar 23;291(5512):2429-33
11264542
J Mol Biol. 2002 Jul 19;320(4):813-20
12095257
Proteins. 2004 Nov 15;57(3):433-43
15382234
J Mol Biol. 2008 Apr 18;378(1):1-11
18353365
Science. 2006 Sep 15;313(5793):1638-42
16973882
J Biol Chem. 2002 Aug 23;277(34):30838-43
12068014
Nat Cell Biol. 2000 Jul;2(7):423-7
10878807
Protein Sci. 2002 Feb;11(2):184-97
11790828
Nature. 1995 Jun 22;375(6533):691-4
7791903
Trends Pharmacol Sci. 2006 Sep;27(9):475-81
16889837
Protein Sci. 2000 Jan;9(1):10-9
10739242
Trends Pharmacol Sci. 2009 Mar;30(3):148-55
19201489
Nat Rev Mol Cell Biol. 2008 May;9(5):402-12
18431400
Curr Pharm Biotechnol. 2006 Jun;7(3):217-23
16789906
Protein Eng. 1999 Sep;12(9):713-20
10506280
Nat Rev Mol Cell Biol. 2005 Nov;6(11):827-37
16227978
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19813-8
18077413
J Biol Chem. 2002 Nov 8;277(45):43168-74
12205094
Proc Natl Acad Sci U S A. 1985 Aug;82(15):5000-4
3860839
Cell. 2002 Aug 9;110(3):281-4
12176314
Structure. 2007 Mar;15(3):341-54
17355869
Acta Crystallogr D Biol Crystallogr. 2002 Jun;58(Pt 6  No 1):899-907
12037327
Science. 2008 Oct 10;322(5899):265-8
18845756
Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2259-64
14982997
Proteins. 2006 Jun 1;63(4):846-67
16475196
Nat Chem Biol. 2008 Aug;4(8):491-7
18604202
Cell Death Differ. 2009 Feb;16(2):187-94
18974774
Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):6887-8
19416924
Nat Chem Biol. 2008 Aug;4(8):474-82
18641628
Science. 1999 Oct 8;286(5438):295-9
10514373
Biochemistry. 1966 Jan;5(1):365-85
5938952
Nat Struct Biol. 2003 Jan;10(1):59-69
12483203
Eur Biophys J. 1984;11(2):103-9
6544679
PLoS Comput Biol. 2007 Jun;3(6):e117
17571919
FASEB J. 2007 Jul;21(9):2124-34
17371796
J Mol Biol. 1992 Apr 5;224(3):733-40
1569552
Nat Rev Mol Cell Biol. 2007 Jul;8(7):530-41
17585314
J Mol Biol. 2007 Nov 16;374(1):121-9
17920628
J Mol Biol. 1990 Aug 5;214(3):613-7
2388258
Mol Biosyst. 2009 Mar;5(3):207-16
19225609
Curr Opin Cell Biol. 2000 Apr;12(2):211-6
10712921
Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):9970-2
10468538
PLoS Comput Biol. 2009 Feb;5(2):e1000293
19229311
Mol Pharmacol. 2008 Sep;74(3):834-43
18552124
J Mol Biol. 2008 Sep 19;381(5):1157-67
18590738
Science. 2005 Jun 3;308(5727):1424-8
15933191
Cell. 1999 Aug 20;98(4):501-12
10481914
Nature. 2002 Jan 31;415(6871):549-53
11823864
Oncogene. 2005 Nov 3;24(48):7238-47
16170383
Cell. 2009 May 15;137(4):609-22
19450511
J Immunol. 2008 May 15;180(10):6977-87
18453620
Nat Rev Immunol. 2007 Jun;7(6):454-65
17525754