The crystal structure of the active form of the C-terminal kinase domain of mitogen- and stress-activated protein kinase 1.
Mitogen- and stress-activated protein kinase 1 (MSK1) is a growth-factor-stimulated serine/threonine kinase that is involved in gene transcription regulation and proinflammatory cytokine stimulation. MSK1 is a dual kinase possessing two nonidentical protein kinase domains in one polypeptide. We present the active conformation of the crystal structures of its C-terminal kinase domain in apo form and in complex with a nonhydrolyzable ATP analogue at 2.0 A and 2.5 A resolutions, respectively. Structural analysis revealed substantial differences in the contacts formed by the C-terminal helix, which is responsible for the inactivity of other autoinhibited kinases. In the C-terminal kinase domain of MSK1, the C-terminal alphaL-helix is located in the surface groove, but forms no hydrogen bonds with the substrate-binding loop or nearby helices, and does not interfere with the protein's autophosphorylation activity. Mutational analysis confirmed that the alphaL-helix is inherently nonautoinhibitory. Overexpression of the single C-terminal kinase domain in JB6 cells resulted in tumor-promoter-induced neoplastic transformation in a manner similar to that induced by the full-length MSK1 protein. The overall results suggest that the C-terminal kinase domain of MSK1 is regulated by a novel alphaL-helix-independent mechanism, suggesting that a diverse mechanism of autoinhibition and activation might be adopted by members of a closely related protein kinase family.
Malakhova
Margarita
M
The Hormel Institute University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
D'Angelo
Igor
I
Kim
Hong-Gyum
HG
Kurinov
Igor
I
Bode
Ann M
AM
Dong
Zigang
Z
D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000737:chemistry*
D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
15299374
Science. 2002 Dec 6;298(5600):1912-34
12471243
EMBO J. 1998 Aug 3;17(15):4426-41
9687510
Structure. 2003 Jun;11(6):627-36
12791252
Oncogene. 2003 Feb 6;22(5):746-55
12569367
Curr Opin Cell Biol. 2009 Apr;21(2):317-24
19217767
J Mol Biol. 2007 Jun 8;369(3):735-45
17449059
Mol Cell Biol. 2002 Apr;22(8):2871-81
11909979
Acta Crystallogr D Biol Crystallogr. 2002 Nov;58(Pt 11):1948-54
12393927
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6353-8
17395714
J Neurosci. 2004 May 5;24(18):4324-32
15128846
Microbiol Mol Biol Rev. 2004 Jun;68(2):320-44
15187187
Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21
9757107
EMBO J. 2008 Jun 18;27(12):1682-93
18511904
J Biol Chem. 1998 Nov 6;273(45):29661-71
9792677
J Med Chem. 2007 May 31;50(11):2647-54
17480064
Methods Enzymol. 1997;276:307-26
27754618
Mol Cell Biol. 2009 Apr;29(8):2105-17
19223461
J Biol Chem. 2007 Mar 30;282(13):9733-9739
17255097
Biochem J. 2005 Sep 15;390(Pt 3):749-59
15910281
FEBS Lett. 2000 Sep 29;482(1-2):44-8
11018520
Curr Biol. 1998 Sep 24;8(19):1049-57
9768359
Structure. 2004 Jun;12(6):1067-77
15274926
Nat Immunol. 2008 Sep;9(9):1028-36
18690222
Proteins. 2007 Feb 15;66(3):630-45
17152079
J Biol Chem. 1999 Aug 6;274(32):22135-8
10428774
Nat Struct Mol Biol. 2008 Jan;15(1):112-3
18084304
Cancer Res. 2008 Apr 1;68(7):2538-47
18381464
Acta Crystallogr D Biol Crystallogr. 2001 Oct;57(Pt 10):1373-82
11567148
EMBO J. 1998 Jun 15;17(12):3363-71
9628873
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
15572765
BMC Mol Biol. 2003 May 26;4:6
12769834
Mol Cell. 2006 Nov 3;24(3):367-81
17081988
J Biol Chem. 2001 Feb 23;276(8):5892-9
11035004
Biochem J. 2007 Mar 15;402(3):491-501
17117922
Mol Cell. 2000 Jun;5(6):905-15
10911985
J Biol Chem. 2002 Oct 4;277(40):37401-5
12171911
EMBO J. 2003 Jun 2;22(11):2788-97
12773393
J Comput Aided Mol Des. 1996 Jun;10(3):255-62
8808741
Biochem J. 2005 Apr 15;387(Pt 2):507-17
15568999
J Biol Chem. 2006 May 5;281(18):12521-5
16517600