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Structural basis for MEKK2 dimerization and substrate recognition.

Kimberly J Vish1, Clotilde Huet-Calderwood2, Byung Hak Ha2

  • 1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.

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|November 29, 2025
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Summary
This summary is machine-generated.

Mitogen-Activated Protein Kinase Kinase Kinases (MAP3K) like MEKK2 exhibit promiscuous signaling. This study reveals MEKK2 dimerization mechanisms and substrate recruitment, providing a framework for understanding MAP3K signaling diversity.

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Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Structural Biology

Background:

  • Mitogen-Activated Protein Kinase Kinase Kinases (MAP3K) signaling pathways are crucial in cellular processes.
  • The precise mechanisms by which MAP3Ks, such as MEKK2, target and activate diverse substrates remain incompletely understood.
  • Understanding substrate specificity is key to deciphering complex cellular signaling networks.

Purpose of the Study:

  • To elucidate the structural basis of MEKK2 dimerization and substrate interaction.
  • To investigate the role of specific MEKK2 structural features in autophosphorylation and substrate recruitment.
  • To provide a framework for understanding substrate targeting by MEKK2 and related MAP3Ks.

Main Methods:

  • Determined the crystal structure of the MEKK2 kinase domain complexed with the inhibitor ponatinib.
  • Assessed the importance of the identified dimerization surface for MEKK2 autophosphorylation and dimerization.
  • Investigated the role of this surface in the phosphorylation and recruitment of MAP2K substrates MEK5 and MKK6.

Main Results:

  • The crystal structure revealed MEKK2 dimerization via a surface involving the αG helix and activation segment.
  • This dimerization interface is critical for MEKK2 autophosphorylation and is conserved in MEKK3.
  • MEK5 and MKK6 phosphorylation by MEKK2 requires the αG helix interaction, but substrate recruitment differs: MEK5 uses PB1 domains, while MKK6 uses the αG helix interface.

Conclusions:

  • The αG helix-mediated dimerization surface is a key determinant for MEKK2 substrate phosphorylation.
  • MEKK2 employs distinct mechanisms for recruiting different substrates, highlighting the complexity of MAP3K signaling.
  • This structural and functional framework advances the understanding of substrate specificity within the MAP3K family.