Multi-state recognition pathway of the intrinsically disordered protein kinase inhibitor by protein kinase A.
Active Transport, Cell Nucleus
Animals
Cyclic AMP-Dependent Protein Kinases
/ genetics
Cytoplasm
Escherichia coli
Intracellular Signaling Peptides and Proteins
/ genetics
Karyopherins
/ genetics
Magnetic Resonance Spectroscopy
Markov Chains
Mice
Protein Kinase Inhibitors
/ metabolism
Rabbits
Receptors, Cytoplasmic and Nuclear
/ genetics
Exportin 1 Protein
E. coli
isotopic labeling
molecular biophysics
protein expression
recombinant dna
structural biology
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
27 04 2020
27 04 2020
Historique:
received:
30
01
2020
accepted:
27
04
2020
pubmed:
28
4
2020
medline:
25
3
2021
entrez:
28
4
2020
Statut:
epublish
Résumé
In the nucleus, the spatiotemporal regulation of the catalytic subunit of cAMP-dependent protein kinase A (PKA-C) is orchestrated by an intrinsically disordered protein kinase inhibitor, PKI, which recruits the CRM1/RanGTP nuclear exporting complex. How the PKA-C/PKI complex assembles and recognizes CRM1/RanGTP is not well understood. Using NMR, SAXS, fluorescence, metadynamics, and Markov model analysis, we determined the multi-state recognition pathway for PKI. After a fast binding step in which PKA-C selects PKI's most competent conformations, PKI folds upon binding through a slow conformational rearrangement within the enzyme's binding pocket. The high-affinity and pseudo-substrate regions of PKI become more structured and the transient interactions with the kinase augment the helical content of the nuclear export sequence, which is then poised to recruit the CRM1/RanGTP complex for nuclear translocation. The multistate binding mechanism featured by PKA-C/PKI complex represents a paradigm on how disordered, ancillary proteins (or protein domains) are able to operate multiple functions such as inhibiting the kinase while recruiting other regulatory proteins for nuclear export.
Identifiants
pubmed: 32338601
doi: 10.7554/eLife.55607
pii: 55607
pmc: PMC7234811
doi:
pii:
Substances chimiques
Intracellular Signaling Peptides and Proteins
0
Karyopherins
0
Protein Kinase Inhibitors
0
Receptors, Cytoplasmic and Nuclear
0
Cyclic AMP-Dependent Protein Kinases
EC 2.7.11.11
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR032961
Pays : United States
Organisme : NIGMS NIH HHS
ID : GM 46736
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM100310
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139065
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM130389
Pays : United States
Informations de copyright
© 2020, Olivieri et al.
Déclaration de conflit d'intérêts
CO, YW, GL, MV, JK, BS, MN, FP, JM, DT, JG, DB, ST, GV No competing interests declared
Références
J Appl Crystallogr. 2017 Jun 26;50(Pt 4):1212-1225
pubmed: 28808438
J Am Chem Soc. 2008 Dec 24;130(51):17629
pubmed: 19583332
J Am Chem Soc. 2012 Apr 18;134(15):6846-54
pubmed: 22414027
Proc Natl Acad Sci U S A. 2015 Mar 24;112(12):3716-21
pubmed: 25775607
J Biomol NMR. 2001 Oct;21(2):141-51
pubmed: 11727977
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3023-8
pubmed: 19204278
J Biol Chem. 1981 Apr 25;256(8):3743-50
pubmed: 6260776
J Biomol NMR. 2007 Nov;39(3):177-85
pubmed: 17828465
J Chem Theory Comput. 2008 Mar;4(3):435-47
pubmed: 26620784
J Otolaryngol Head Neck Surg. 2011 Feb;40(1):27-33
pubmed: 21303598
Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):E7959-E7968
pubmed: 28855336
Nat Commun. 2014 Dec 05;5:5680
pubmed: 25477193
J Biol Chem. 1995 Mar 31;270(13):7227-32
pubmed: 7706262
Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1374-9
pubmed: 25605907
Nat Chem Biol. 2011 Apr;7(4):214-21
pubmed: 21358637
Bioinformatics. 2015 Apr 15;31(8):1325-7
pubmed: 25505092
Front Mol Biosci. 2016 Sep 09;3:52
pubmed: 27668217
Anal Biochem. 1997 Feb 15;245(2):115-22
pubmed: 9056191
Biochemistry. 1989 Jul 25;28(15):6150-6
pubmed: 2675964
Science. 1988 Jul 1;241(4861):42-52
pubmed: 3291115
Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6278-83
pubmed: 18434548
Chem Rev. 2001 Aug;101(8):2243-70
pubmed: 11749372
FEBS Lett. 2015 Sep 14;589(19 Pt A):2570-7
pubmed: 26320411
J Am Chem Soc. 2018 Jan 24;140(3):1148-1158
pubmed: 29276882
Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14231-6
pubmed: 23946424
Biochemistry. 1999 May 25;38(21):6774-80
pubmed: 10346898
Science. 2019 Dec 13;366(6471):
pubmed: 31831640
J Am Chem Soc. 2001 Apr 4;123(13):2970-8
pubmed: 11457007
Molecules. 2018 Aug 03;23(8):
pubmed: 30081441
Phys Chem Chem Phys. 2014 Apr 14;16(14):6323-31
pubmed: 24317797
Methods Mol Biol. 2012;895:387-404
pubmed: 22760329
Chem Rev. 2009 Sep;109(9):4108-39
pubmed: 19522502
Prog Nucl Magn Reson Spectrosc. 2013 Aug;73:1-16
pubmed: 23962882
Neuropeptides. 2006 Feb;40(1):23-34
pubmed: 16442618
J Biol Chem. 1971 Apr 10;246(7):1977-85
pubmed: 4324557
J Biomol NMR. 1999 Jan;13(1):3-10
pubmed: 21080259
J Biomol NMR. 2000 Sep;18(1):43-8
pubmed: 11061227
Elife. 2015 Sep 08;4:
pubmed: 26349033
Science. 1991 Jul 26;253(5018):407-14
pubmed: 1862342
Chem Rev. 2001 Aug;101(8):2209-42
pubmed: 11749371
Protein Sci. 1999 Mar;8(3):545-53
pubmed: 10091657
J Mol Biol. 2007 Apr 13;367(5):1494-510
pubmed: 17320108
J Biomol NMR. 1994 Sep;4(5):727-34
pubmed: 7919956
Nat Struct Mol Biol. 2010 Nov;17(11):1367-76
pubmed: 20972448
J Mol Recognit. 2010 Mar-Apr;23(2):105-16
pubmed: 19585546
Biochemistry. 1990 May 15;29(19):4659-67
pubmed: 2372549
J Biol Chem. 1993 Sep 5;268(25):18626-32
pubmed: 8395513
J Biol Chem. 1997 Jul 18;272(29):18169-78
pubmed: 9218452
J Chem Phys. 2013 Feb 28;138(8):084107
pubmed: 23464140
Nat Chem Biol. 2010 Nov;6(11):821-8
pubmed: 20890288
J Biomol NMR. 1995 Nov;6(3):277-93
pubmed: 8520220
J Biol Chem. 1992 Aug 25;267(24):16824-8
pubmed: 1512225
Biophys J. 2013 Aug 20;105(4):962-74
pubmed: 23972848
Nature. 2015 Mar 5;519(7541):106-9
pubmed: 25533957
Biochem Soc Trans. 2014 Feb;42(1):139-44
pubmed: 24450641
Mol Biol Cell. 2018 Aug 15;29(17):2037-2044
pubmed: 29927350
J Am Chem Soc. 2001 Feb 7;123(5):967-75
pubmed: 11456632
Biopolymers. 1996 Sep;39(3):353-65
pubmed: 8756515
J Biol Chem. 1999 Mar 5;274(10):6381-7
pubmed: 10037729
Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):506-11
pubmed: 18178622
Cell. 1995 Aug 11;82(3):463-73
pubmed: 7634336
Nat Cell Biol. 2002 Aug;4(8):E203-6
pubmed: 12149635
J Comput Chem. 2014 May 30;35(14):1101-5
pubmed: 24676684
J Biol Chem. 1986 Jan 25;261(3):989-92
pubmed: 3511044
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1388-93
pubmed: 16432188
Nat Rev Mol Cell Biol. 2012 Oct;13(10):646-58
pubmed: 22992589
Sci Adv. 2019 Aug 28;5(8):eaaw9298
pubmed: 31489371
Biochemistry. 1994 May 17;33(19):5984-6003
pubmed: 7514039
Biophys J. 2017 Jan 10;112(1):10-15
pubmed: 28076801
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13585-90
pubmed: 9811843
J Biol Chem. 1991 Jun 15;266(17):10906-11
pubmed: 2040607
Biochemistry. 1989 Nov 14;28(23):8972-9
pubmed: 2690953
Methods Enzymol. 2001;339:204-38
pubmed: 11462813
Science. 1997 Nov 7;278(5340):1111-4
pubmed: 9353189
Chem Rev. 2004 Aug;104(8):3607-22
pubmed: 15303830
Curr Opin Struct Biol. 2006 Dec;16(6):702-9
pubmed: 17079130
Biophys Chem. 2014 May;189:33-9
pubmed: 24747333
J Mol Biol. 1999 Sep 10;292(1):111-23
pubmed: 10493861
Biochemistry. 1992 Jun 16;31(23):5269-78
pubmed: 1606151
J Phys Chem B. 2015 Jan 22;119(3):653-61
pubmed: 24824082
Recent Prog Horm Res. 1973;29:329-59
pubmed: 4356274
Trends Biochem Sci. 2019 Apr;44(4):300-311
pubmed: 30611608
J Biomol NMR. 2018 Mar;70(3):133-140
pubmed: 29396770
Nat Chem Biol. 2009 Nov;5(11):808-14
pubmed: 19841630
J Chem Theory Comput. 2012 Sep 11;8(9):3257-3273
pubmed: 23341755
Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):9882-9887
pubmed: 28847960
Proc Natl Acad Sci U S A. 2015 Nov 17;112(46):14272-7
pubmed: 26578772
J Biol Chem. 1982 Jun 10;257(11):6028-32
pubmed: 7076663
Science. 1991 Jul 26;253(5018):414-20
pubmed: 1862343
Elife. 2017 Mar 10;6:
pubmed: 28282025
J Pept Res. 1997 Mar;49(3):210-20
pubmed: 9151254
J Magn Reson. 2000 May;144(1):123-8
pubmed: 10783281
Biomol NMR Assign. 2009 Jun;3(1):115-7
pubmed: 19636960
Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):1891-6
pubmed: 21245357
Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3409-14
pubmed: 25737554
J Magn Reson. 1998 Apr;131(2):373-8
pubmed: 9571116
Nat Rev Mol Cell Biol. 2015 Jan;16(1):18-29
pubmed: 25531225
J Magn Reson. 2011 Dec;213(2):423-41
pubmed: 22152361
Nucleic Acids Res. 2018 Jul 2;46(W1):W315-W322
pubmed: 29893907
J Biol Chem. 1980 Feb 25;255(4):1559-64
pubmed: 6243641
Biochemistry. 2012 Mar 20;51(11):2224-31
pubmed: 22360139
J Magn Reson. 2007 Feb;184(2):185-95
pubmed: 17084097