Structural diversity in free and bound states of intrinsically disordered protein phosphatase 1 regulators.
Complete folding is not a prerequisite for protein function, as disordered and partially folded states of proteins frequently perform essential biological functions. In order to understand their functions at the molecular level, we utilized diverse experimental measurements to calculate ensemble models of three nonhomologous, intrinsically disordered proteins: I-2, spinophilin, and DARPP-32, which bind to and regulate protein phosphatase 1 (PP1). The models demonstrate that these proteins have dissimilar propensities for secondary and tertiary structure in their unbound forms. Direct comparison of these ensemble models with recently determined PP1 complex structures suggests a significant role for transient, preformed structure in the interactions of these proteins with PP1. Finally, we generated an ensemble model of partially disordered I-2 bound to PP1 that provides insight into the relationship between flexibility and biological function in this dynamic complex.
Marsh
Joseph A
JA
Molecular Structure & Function, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Dancheck
Barbara
B
Ragusa
Michael J
MJ
Allaire
Marc
M
Forman-Kay
Julie D
JD
Peti
Wolfgang
W
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000737:chemistry / Q000378:metabolism; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D054645:Protein Phosphatase 1 / Q000737:chemistry* / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099273:Neurabins; D000097847:Protein Phosphatase Inhibitory Proteins
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D054645:Protein Phosphatase 1; D011506:Proteins; D000099273:Neurabins; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins
Nature. 1984 Aug 9-15;310(5977):503-5
6087160
Biochemistry. 2007 Mar 6;46(9):2380-9
17286390
Biochemistry. 1999 Apr 6;38(14):4365-73
10194355
Nat Biotechnol. 2001 Sep;19(9):805-6
11533628
J Biol Chem. 2003 May 23;278(21):18817-23
12657641
Biophys J. 2001 Jun;80(6):2946-53
11371467
Nature. 2004 Jun 17;429(6993):780-4
15164081
Biochemistry. 2005 Sep 20;44(37):12454-70
16156658
Biochemistry. 2008 Nov 25;47(47):12346-56
18954090
J Cell Sci. 2002 Jan 15;115(Pt 2):241-56
11839776
Biochimie. 2006 Sep;88(9):1099-113
16737766
Proteins. 2000 May 1;39(2):112-31
10737933
Nature. 2007 Jun 21;447(7147):1021-5
17522630
J Mol Biol. 2009 Jan 9;385(1):11-21
18992256
Biochemistry. 2007 Nov 27;46(47):13468-77
17973494
Bioessays. 2002 Apr;24(4):371-81
11948623
Proteins. 2003 Dec 1;53(4):855-62
14635127
Biochemistry. 1972 Feb 29;11(5):864-78
5059892
Biochimie. 2007 Mar;89(3):419-21
17174464
J Biol Chem. 1994 Nov 18;269(46):28919-28
7961854
Eur J Biochem. 2002 Jan;269(1):2-12
11784292
Cell. 2007 May 4;129(3):579-91
17482550
Biochemistry. 1991 Oct 22;30(42):10280-7
1657143
J Mol Biol. 2007 Apr 13;367(5):1494-510
17320108
Biochemistry. 2005 Mar 15;44(10):3955-64
15751971
J Mol Recognit. 2010 Mar-Apr;23(2):105-16
19585546
J Mol Biol. 1999 Oct 22;293(2):321-31
10550212
Biochemistry. 2008 Dec 9;47(49):12942-4
19012413
Neuropharmacology. 2004;47 Suppl 1:14-23
15464122
Proc Natl Acad Sci U S A. 1958 Feb;44(2):98-104
16590179
J Mol Biol. 2001 May 18;308(5):1011-32
11352588
FEBS Lett. 2005 Jun 13;579(15):3346-54
15943980
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3080-5
11248035
J Mol Biol. 2002 Oct 25;323(3):573-84
12381310
Curr Opin Struct Biol. 2002 Feb;12(1):54-60
11839490
J Biol Chem. 1994 Jan 14;269(2):944-54
8288648
Mol Biol Cell. 2008 Nov;19(11):4852-62
18716057
J Mol Biol. 2009 Aug 14;391(2):359-74
19501099
Biochemistry. 2008 Jan 8;47(1):292-300
18062707
Neuron. 2001 Dec 20;32(6):1133-48
11754843
Nat Struct Mol Biol. 2010 Apr;17(4):459-64
20305656
Proteins. 2000 Nov 15;41(3):415-27
11025552
Trends Biochem Sci. 2001 Jul;26(7):426-31
11440854
Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8625-30
15173575
Proteins. 1995 Dec;23(4):566-79
8749853
Trends Biochem Sci. 2008 Jan;33(1):2-8
18054235
J Proteome Res. 2007 Jun;6(6):2351-66
17488107
Trends Biochem Sci. 2002 Oct;27(10):527-33
12368089
J Biol Chem. 2007 Sep 28;282(39):28874-28883
17636256
J Mol Biol. 2006 Oct 6;362(5):1043-59
16935303
J Appl Crystallogr. 2009 Apr 1;42(Pt 2):342-346
27630371
Protein Sci. 2002 Apr;11(4):739-56
11910019
J Mol Graph Model. 2001;19(1):26-59
11381529
J Biol Chem. 1984 May 10;259(9):5864-70
6325452
Biochemistry. 2002 May 28;41(21):6573-82
12022860
Biophys J. 2000 Feb;78(2):719-30
10653785