Structural assembly of the signaling competent ERK2-RSK1 heterodimeric protein kinase complex

Area of Science:

• Molecular biology
• Biochemistry
• Structural biology

Background:

• Mitogen-activated protein kinases (MAPKs) regulate cellular processes by activating downstream MAPK-activated protein kinases (MAPKAPKs).
• Extracellular signal regulated kinase 2 (ERK2) phosphorylates ribosomal S6 kinase 1 (RSK1), a key mediator of cellular growth.

Purpose of the Study:

• To determine the crystal structure of RSK1 in complex with its activator, ERK2.
• To elucidate the molecular mechanisms underlying MAPK-MAPKAPK complex formation and activation.

Main Methods:

• X-ray crystallography to obtain the structure of the ERK2-RSK1 complex.
• Molecular dynamics simulations to model the transition to an active state.
• Biochemical and cellular assays to validate the role of specific interactions.

Main Results:

• The crystal structure revealed a precatalytic complex with RSK1's activation loop near ERK2's catalytic site.
• A MAPK binding linear motif on RSK1 interacts with ERK2's docking groove, forming the initial encounter complex.
• Subsequent domain readjustment and surface contacts facilitate the transition to a catalytically competent state.

Conclusions:

• The interaction between the MAPK binding motif and the ERK2 docking groove is essential for initiating the MAPK-MAPKAPK complex.
• Structural and dynamic insights explain how ERK2 activates RSK1, promoting cellular growth signaling pathways.