Abstract

The catalytic activities of eukaryotic protein kinases (EPKs) are regulated by movement of the C-helix, movement of the N and C lobes upon ATP binding, and movement of the activation loop upon phosphorylation. Statistical analysis of the selective constraints associated with AGC kinase functional divergence reveals conserved interactions between these regulatory regions and three regions of the C-terminal tail (C-tail): the N-lobe tether (NLT), the active-site tether (AST), and the C-lobe tether (CLT). The NLT serves as a docking site for an upstream kinase PDK1 and, upon activation, positions the C-helix within the ATP binding pocket. The AST directly interacts with the ATP binding pocket, and the CLT interacts with the interlobe linker and the αC–β4 loop, which appears to serve as a hinge for C-helix movement. The C-tail is a hallmark of AGC functional divergence inasmuch as most of the conserved core residues that distinguish AGC kinases from other EPKs are associated with the NLT, AST, or CLT. Moreover, several AGC catalytic core conserved residues that interact with the C-tail strikingly diverge from the canonical residues observed at corresponding positions in nearly all other EPKs, suggesting that the catalytic core may have coevolved with the C-tail in AGC kinases. These observations, along with the fact that the C-tail is needed for catalytic activity suggests that the C-tail is a cis-acting regulatory module that can also serve as a regulatory “handle,” to which trans-acting cellular components can bind to modulate activity.

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Acknowledgments

We thank members of S.S.T.'s laboratory and Alexandra Newton's laboratory (University of California at San Diego) for helpful discussions. This work was funded by National Institutes of Health Grant IP01DK54441 (to S.S.T.), National Library of Medicine Grant LM06747 (to A.F.N.), and National Institutes of Health Division of General Medicine Grant GM078541 (to A.F.N.).

Supporting Information

Adobe PDF - 10251Appendix1.pdf
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Adobe PDF - 10251Appendix2.pdf
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Adobe PDF - 10251Appendix3.pdf
Adobe PDF - 10251Appendix3.pdf

References

1
SK Hanks, T Hunter FASEB J 9, 576–596 (1995).
2
G Manning, DB Whyte, R Martinez, T Hunter, S Sudarsanam Science 298, 1912–1934 (2002).
3
LN Johnson, ME Noble, DJ Owen Cell 85, 149–158 (1996).
4
M Huse, J Kuriyan Cell 109, 275–282 (2002).
5
B Nolen, S Taylor, G Ghosh Mol Cell 15, 661–675 (2004).
6
DR Alessi, SR James, CP Downes, AB Holmes, PR Gaffney, CB Reese, P Cohen Curr Biol 7, 261–269 (1997).
7
N Pullen, PB Dennis, M Andjelkovic, A Dufner, SC Kozma, BA Hemmings, G Thomas Science 279, 707–710 (1998).
8
EM Dutil, A Toker, AC Newton Curr Biol 8, 1366–1375 (1998).
9
X Cheng, Y Ma, M Moore, BA Hemmings, SS Taylor Proc Natl Acad Sci USA 95, 9849–9854 (1998).
10
C Belham, S Wu, J Avruch Curr Biol 9, R93–R96 (1999).
11
RT Peterson, SL Schreiber Curr Biol 9, R521–R524 (1999).
12
RA Currie, KS Walker, A Gray, M Deak, A Casamayor, CP Downes, P Cohen, DR Alessi, J Lucocq Biochem J 337, 575–583 (1999).
13
CC Milburn, M Deak, SM Kelly, NC Price, DR Alessi, DM Van Aalten Biochem J 375, 531–538 (2003).
14
CC Thomas, M Deak, DR Alessi, DM van Aalten Curr Biol 12, 1256–1262 (2002).
15
EA Nalefski, AC Newton Biochemistry 40, 13216–13229 (2001).
16
ID Fraser, SJ Tavalin, LB Lester, LK Langeberg, AM Westphal, RA Dean, NV Marrion, JD Scott EMBO J 17, 2261–2272 (1998).
17
J Struppe, EA Komives, SS Taylor, RR Vold Biochemistry 37, 15523–15527 (1998).
18
PD Jeffrey, AA Russo, K Polyak, E Gibbs, J Hurwitz, J Massague, NP Pavletich Nature 376, 313–320 (1995).
19
J Yang, P Cron, V Thompson, VM Good, D Hess, BA Hemmings, D Barford Mol Cell 9, 1227–1240 (2002).
20
DR Knighton, JH Zheng, LF Ten Eyck, VA Ashford, NH Xuong, SS Taylor, JM Sowadski Science 253, 407–414 (1991).
21
A Balendran, RM Biondi, PC Cheung, A Casamayor, M Deak, DR Alessi J Biol Chem 275, 20806–20813 (2000).
22
RM Biondi, PC Cheung, A Casamayor, M Deak, RA Currie, DR Alessi EMBO J 19, 979–988 (2000).
23
T Gao, A Toker, AC Newton J Biol Chem 276, 19588–19596 (2001).
24
RC Hresko, M Mueckler J Biol Chem 280, 40406–40416 (2005).
25
DD Sarbassov, DA Guertin, SM Ali, DM Sabatini Science 307, 1098–1101 (2005).
26
M Frodin, CJ Jensen, K Merienne, S Gammeltoft EMBO J 19, 2924–2934 (2000).
27
AF Neuwald, N Kannan, A Poleksic, N Hata, JS Liu Genome Res 13, 673–692 (2003).
28
AF Neuwald Trends Biochem Sci 31, 374–382 (2006).
29
N Kannan, AF Neuwald J Mol Biol 351, 956–972 (2005).
30
N Narayana, S Cox, X Nguyen-huu, LF Ten Eyck, SS Taylor Structure (London) 5, 921–935 (1997).
31
A Chestukhin, L Litovchick, D Schourov, S Cox, SS Taylor, S Shaltiel J Biol Chem 271, 10175–10182 (1996).
32
MB Lamers, AA Antson, RE Hubbard, RK Scott, DH Williams J Mol Biol 285, 713–725 (1999).
33
I Tsigelny, BD Grant, SS Taylor, LF Ten Eyck Biopolymers 39, 353–365 (1996).
34
S Hayward J Mol Biol 339, 1001–1021 (2004).
35
DT Lodowski, JA Pitcher, WD Capel, RJ Lefkowitz, JJ Tesmer Science 300, 1256–1262 (2003).
36
T Jiang, Y Qiu J Biol Chem 278, 15789–15793 (2003).
37
RP Bhattacharyya, A Remenyi, MC Good, CJ Bashor, AM Falick, WA Lim Science 311, 822–826 (2006).
38
T Zhou, L Sun, J Humphreys, EJ Goldsmith Structure (London) 14, 1011–1019 (2006).
39
B Nolen, J Ngo, S Chakrabarti, D Vu, JA Adams, G Ghosh Biochemistry 42, 9575–9585 (2003).
40
AK Padyana, H Qiu, A Roll-Mecak, AG Hinnebusch, SK Burley J Biol Chem 280, 29289–29299 (2005).
41
JT Nguyen, CW Turck, FE Cohen, RN Zuckermann, WA Lim Science 282, 2088–2092 (1998).
42
WA Lim, FM Richards, RO Fox Nature 372, 375–379 (1994).
43
AR Conery, Y Cao, EA Thompson, CM Townsend, TC Ko, K Luo Nat Cell Biol 6, 366–372 (2004).
44
P Akamine, Madhusudan, J Wu, NH Xuong, LF Ten Eyck, SS Taylor J Mol Biol 327, 159–171 (2003).
45
SJ Deminoff, SC Howard, A Hester, S Warner, PK Herman Genetics 173, 1909–1917 (2006).
46
A Balendran, A Casamayor, M Deak, A Paterson, P Gaffney, R Currie, CP Downes, DR Alessi Curr Biol 9, 393–404 (1999).
47
W Zhang, E Crocker, S McLaughlin, SO Smith J Biol Chem 278, 21459–21466 (2003).
48
E Strandberg, S Morein, DT Rijkers, RM Liskamp, PC van der Wel, JA Killian Biochemistry 41, 7190–7198 (2002).
49
J Zheng, DR Knighton, NH Xuong, SS Taylor, JM Sowadski, LF Ten Eyck Protein Sci 2, 1559–1573 (1993).
50
J Yang, LF Ten Eyck, NH Xuong, SS Taylor J Mol Biol 336, 473–487 (2004).

Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 104 | No. 4
January 23, 2007
PubMed: 17227859

Classifications

Submission history

Received: September 26, 2006
Published online: January 23, 2007
Published in issue: January 23, 2007

Keywords

  1. kinase mechanisms
  2. phosphorylation
  3. signaling

Acknowledgments

We thank members of S.S.T.'s laboratory and Alexandra Newton's laboratory (University of California at San Diego) for helpful discussions. This work was funded by National Institutes of Health Grant IP01DK54441 (to S.S.T.), National Library of Medicine Grant LM06747 (to A.F.N.), and National Institutes of Health Division of General Medicine Grant GM078541 (to A.F.N.).

Notes

This article contains supporting information online at www.pnas.org/cgi/content/full/0610251104/DC1.

Authors

Affiliations

Natarajan Kannan
Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0654; and
Nina Haste
Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0654; and
Susan S. Taylor [email protected]
Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0654; and
Andrew F. Neuwald [email protected]
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724

Notes

To whom correspondence may be addressed: E-mail: [email protected] or [email protected]
Contributed by Susan S. Taylor, November 21, 2006

Competing Interests

The authors declare no conflict of interest.

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    The hallmark of AGC kinase functional divergence is its C-terminal tail, a cis-acting regulatory module
    Proceedings of the National Academy of Sciences
    • Vol. 104
    • No. 4
    • pp. 1105-1442

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