Molecular Basis of MAPK-activated Protein Kinase 2:p38 Assembly

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Mar 31

PMID 17395714

Citations 49

Authors

Andre White

Christopher A Pargellis

Joey M Studts

Brian G Werneburg

Bennett T Farmer 2nd

Affiliations

Soon will be listed here.

Abstract

p38 MAPK and MAPK-activated protein kinase 2 (MK2) are key components of signaling pathways leading to many cellular responses, notably the proinflammatory cytokine production. The physical association of p38alpha isoform and MK2 is believed to be physiologically important for this signaling. We report the 2.7-A resolution crystal structure of the unphosphorylated complex between p38alpha and MK2. These protein kinases bind "head-to-head," present their respective active sites on approximately the same side of the heterodimer, and form extensive intermolecular interactions. Among these interactions, the MK2 Ile-366-Ala-390, which includes the bipartite nuclear localization signal, binds to the p38alpha-docking region. This binding supports the involvement of noncatalytic regions to the tight binding of the MK2:p38alpha binary assembly. The MK2 residues 345-365, containing the nuclear export signal, block access to the p38alpha active site. Some regulatory phosphorylation regions of both protein kinases engage in multiple interactions with one another in this complex. This structure gives new insights into the regulation of the protein kinases p38alpha and MK2, aids in the better understanding of their known cellular and biochemical studies, and provides a basis for understanding other regulatory protein-protein interactions involving signal transduction proteins.

Citing Articles

MK2 nonenzymatically promotes nuclear translocation of caspase-3 and resultant apoptosis.

Del Rosario O, Suresh K, Kallem M, Singh G, Shah A, Zheng L Am J Physiol Lung Cell Mol Physiol. 2023; 324(5):L700-L711.

PMID: 36976920 PMC: 10190840. DOI: 10.1152/ajplung.00340.2022.

Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α.

Cubillos-Rojas M, Loren G, Hakim Y, Verdaguer X, Riera A, Nebreda A Cancers (Basel). 2023; 15(3).

PMID: 36765568 PMC: 9913880. DOI: 10.3390/cancers15030611.

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors.

Pantsar T, Kaiser P, Kudolo M, Forster M, Rothbauer U, Laufer S Nat Commun. 2022; 13(1):569.

PMID: 35091547 PMC: 8799644. DOI: 10.1038/s41467-022-28164-4.

Mitogen-activated protein kinase-activated protein kinase-2 (MK2) and its role in cell survival, inflammatory signaling, and migration in promoting cancer.

Morgan D, Berggren K, Spiess C, Smith H, Tejwani A, Weir S Mol Carcinog. 2021; 61(2):173-199.

PMID: 34559922 PMC: 8799529. DOI: 10.1002/mc.23348.

MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate.

Gutierrez-Prat N, Cubillos-Rojas M, Canovas B, Kuzmanic A, Gupta J, Igea A Proc Natl Acad Sci U S A. 2021; 118(29).

PMID: 34272277 PMC: 8307377. DOI: 10.1073/pnas.2024562118.

References

Chew A, Bennett A, Smith C, Barker J, Kirkham B . Successful treatment of severe psoriasis and psoriatic arthritis with adalimumab. Br J Dermatol. 2004; 151(2):492-6. DOI: 10.1111/j.1365-2133.2004.06105.x. View

Leighton I, Doza Y, Attwood P, Morrice N, Marshall C, Cohen P . Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2. EMBO J. 1995; 14(23):5920-30. PMC: 394711. DOI: 10.1002/j.1460-2075.1995.tb00280.x. View

Stoecklin G, Stubbs T, Kedersha N, Wax S, Rigby W, Blackwell T . MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay. EMBO J. 2004; 23(6):1313-24. PMC: 381421. DOI: 10.1038/sj.emboj.7600163. View

Dinarello C . Inflammatory cytokines: interleukin-1 and tumor necrosis factor as effector molecules in autoimmune diseases. Curr Opin Immunol. 1991; 3(6):941-8. DOI: 10.1016/s0952-7915(05)80018-4. View

Nuki G, Bresnihan B, Bear M, McCabe D . Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled.... Arthritis Rheum. 2002; 46(11):2838-46. DOI: 10.1002/art.10578. View

Engel K, Kotlyarov A, Gaestel M . Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation. EMBO J. 1998; 17(12):3363-71. PMC: 1170674. DOI: 10.1093/emboj/17.12.3363. View

Beardmore V, Hinton H, Eftychi C, Apostolaki M, Armaka M, Darragh J . Generation and characterization of p38beta (MAPK11) gene-targeted mice. Mol Cell Biol. 2005; 25(23):10454-64. PMC: 1291241. DOI: 10.1128/MCB.25.23.10454-10464.2005. View

Pargellis C, Regan J . Inhibitors of p38 mitogen-activated protein kinase for the treatment of rheumatoid arthritis. Curr Opin Investig Drugs. 2003; 4(5):566-71. View

Allen M, Svensson L, Roach M, Hambor J, McNeish J, Gabel C . Deficiency of the stress kinase p38alpha results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme-deficient embryonic stem cells. J Exp Med. 2000; 191(5):859-70. PMC: 2195860. DOI: 10.1084/jem.191.5.859. View

10.

Belka C, Ahlers A, Sott C, Gaestel M, Herrmann F, Brach M . Interleukin (IL)-6 signaling leads to phosphorylation of the small heat shock protein (Hsp)27 through activation of the MAP kinase and MAPKAP kinase 2 pathway in monocytes and monocytic leukemia cells. Leukemia. 1995; 9(2):288-94. View

11.

Shi Y, Gaestel M . In the cellular garden of forking paths: how p38 MAPKs signal for downstream assistance. Biol Chem. 2002; 383(10):1519-36. DOI: 10.1515/BC.2002.173. View

12.

Lukas S, Kroe R, Wildeson J, Peet G, Frego L, Davidson W . Catalysis and function of the p38 alpha.MK2a signaling complex. Biochemistry. 2004; 43(31):9950-60. DOI: 10.1021/bi049508v. View

13.

Underwood K, Parris K, Federico E, Mosyak L, Czerwinski R, Shane T . Catalytically active MAP KAP kinase 2 structures in complex with staurosporine and ADP reveal differences with the autoinhibited enzyme. Structure. 2003; 11(6):627-36. DOI: 10.1016/s0969-2126(03)00092-3. View

14.

Zhang W, Wang R, Wisniewski D, Marcy A, LoGrasso P, Lisnock J . Time-resolved Forster resonance energy transfer assays for the binding of nucleotide and protein substrates to p38alpha protein kinase. Anal Biochem. 2005; 343(1):76-83. DOI: 10.1016/j.ab.2005.05.011. View

15.

Zu Y, Ai Y, Huang C . Characterization of an autoinhibitory domain in human mitogen-activated protein kinase-activated protein kinase 2. J Biol Chem. 1995; 270(1):202-6. DOI: 10.1074/jbc.270.1.202. View

16.

Murshudov G, Vagin A, Dodson E . Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr. 1997; 53(Pt 3):240-55. DOI: 10.1107/S0907444996012255. View

17.

POMERANCE M, Quillard J, Chantoux F, Young J, Blondeau J . High-level expression, activation, and subcellular localization of p38-MAP kinase in thyroid neoplasms. J Pathol. 2006; 209(3):298-306. DOI: 10.1002/path.1975. View

18.

Hitti E, Iakovleva T, Brook M, Deppenmeier S, Gruber A, Radzioch D . Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Mol Cell Biol. 2006; 26(6):2399-407. PMC: 1430282. DOI: 10.1128/MCB.26.6.2399-2407.2006. View

19.

Wang Z, Harkins P, Ulevitch R, Han J, Cobb M, Goldsmith E . The structure of mitogen-activated protein kinase p38 at 2.1-A resolution. Proc Natl Acad Sci U S A. 1997; 94(6):2327-32. PMC: 20087. DOI: 10.1073/pnas.94.6.2327. View

20.

Hegen M, Gaestel M, Nickerson-Nutter C, Lin L, Telliez J . MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis. J Immunol. 2006; 177(3):1913-7. DOI: 10.4049/jimmunol.177.3.1913. View