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. 2006 Apr 4;103(14):5326-31.
doi: 10.1073/pnas.0510506103. Epub 2006 Mar 27.

Structural basis of docking interactions between ERK2 and MAP kinase phosphatase 3

Sijiu Liu  1 , Jin-Peng Sun, Bo Zhou, Zhong-Yin Zhang
Affiliations

Structural basis of docking interactions between ERK2 and MAP kinase phosphatase 3

Sijiu Liu et al. Proc Natl Acad Sci U S A. .

Abstract

Mitogen-activated protein (MAP) kinases are central components of signal transduction pathways for cell proliferation, stress responses, and differentiation. Signaling efficiency and specificity are modulated in large part by docking interactions between individual MAP kinase and the kinase interaction motif (KIM), (R/K)(2-3)-X(1-6)-Phi(A)-X-Phi(B), in its cognate kinases, phosphatases, scaffolding proteins, and substrates. We have determined the crystal structure of extracellular signal-regulated protein kinase 2 bound to the KIM peptide from MAP kinase phosphatase 3, an extracellular signal-regulated protein kinase 2-specific phosphatase. The structure reveals that the KIM docking site, situated in a noncatalytic region opposite of the kinase catalytic pocket, is comprised of a highly acidic patch and a hydrophobic groove, which engage the basic and Phi(A)-X-Phi(B) residues, respectively, in the KIM sequence. The specific docking interactions observed in the structure consolidate all known biochemical data. In addition, structural comparison indicates that the KIM docking site is conserved in all MAP kinases. The results establish a structural model for understanding how MAP kinases interact with their regulators and substrates and provide new insights into how MAP kinase docking specificity can be achieved.

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Overall structure of ERK2 bound with KIMMKP3. (a) ERK2 is shown in a ribbon model, and the disordered regions are depicted as dotted lines. The bound peptide is shown in a stick-and-ball model. (b) The Fo − Fc density map for the KIM peptide calculated by using the final model without the peptide and contoured at 2.5σ.
Fig. 2.
Fig. 2.
Detailed interactions between ERK2 and KIMMKP3. (a) Surface representation of ERK2 in complex with KIMMKP3, colored by electrostatic potential. KIM residues are in black, and ERK2 residues are in light blue. (b) Stereo diagram of the docking interactions between ERK2 (orange) and KIMMKP3 (green). ERK2 residues are shown in black, and those of KIMMKP3 are shown in green.
Fig. 3.
Fig. 3.
Stereoview of the superposition of the structures of ERK2, p38α, and JNK1 with the bound KIM peptides highlighted (blue for KIMMKP3, green for KIMMKK3b, red for KIMMEF2A, and orange for KIMJIP1). Residues Arg-64 and Arg-65 of KIMMKP3, Arg-156 of KIMJIP1, and the ΦA and ΦB in all peptides are shown.
Fig. 4.
Fig. 4.
Structural comparison of the ERK2, p38α, and JNK1 docking sites. (a) Structural comparison of the hydrophobic groove in ERK2 (green), p38α (orange), and JNK1 (cyan). ERK2 residues that contribute to hydrophobic interactions with the ΦA and ΦB residues are shown. (b) Structural comparison of the acidic patch in ERK2 (green), p38α (orange), and JNK1 (cyan). ERK2 residues that interact directly with the basic residues are shown.
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