The mitogen-activated protein kinases (MAPKs) are vital components of eukaryotic signal transduction networks, ensuring appropriate cellularresponses to diverse extracellular stimuli. Among the three major MAPK pathways, the c-Jun N-terminal kinase (JNK) cascade is essential for regulating stress responses and apoptosis. The homologous scaffold proteins JIP1 and JIP2 play a critical role in the JNK signalling pathway by assembling multiple kinases to enhance the efficiency and specificity of signal transduction. Although JIP1 and JIP2 are known to form both homo- and heterodimers via their Src-homology 3 (SH3) domains, the structural basis of these interactions was previously unknown.
In a collaborative study, researchers from the IBS (SIGNAL group), the IAB (Andrés Palencia’s group), and the University of Massachusetts (Roger Davis’ group) solved the crystal structures of the JIP2-SH3 homodimer and the JIP1-JIP2-SH3 heterodimer. The JIP2-SH3 homodimer structure reveals a reorganisation of salt bridges and hydrogen bonds at its dimerization interface compared to JIP1-SH3. The structure of the JIP1-JIP2-SH3 complex shows how features of both homo-dimers are integrated to stabilize the heterodimer. By mutating key residues involved in dimer stabilization of both JIP1 and JIP2 in cellulo, the researchers could demonstrate that dimerization has a significant impact on JNK pathway activation. This work highlights how heterodimerization of scaffold proteins may serve as a regulatory mechanism to fine-tune signal transduction and modulate cellular responses.
Structural basis of homodimerization of the JNK scaffold protein JIP2 and its heterodimerization with JIP1. Mariño Pérez L, Ielasi FS, Lee A, Delaforge E, Juyoux P, Tengo M, Davis RJ, Palencia A, Jensen MR. Structure 2024 ; 32, 1394-1403.e5
Contact : Malene R. Jensen (IBS/ Structural Dynamics of Signalling Complexes Group)