ZAK activation at the collided ribosome

Area of Science:

• Molecular Biology
• Cellular Stress Response
• Protein Kinase Signaling

Background:

• Ribosome collisions trigger the ribotoxic stress response, involving ZAK kinase and downstream MAPKs.
• The precise mechanisms of ZAK-ribosome interaction and activation are not well understood.

Purpose of the Study:

• To elucidate the structural and mechanistic basis of ZAK kinase activation by ribosome collisions.
• To identify key interactions between ZAK, ribosomes, and regulatory proteins.

Main Methods:

• Biochemistry
• Cryo-electron microscopy (cryo-EM)
• Analysis of ZAK SAM domain variants

Main Results:

• Distinct ZAK-ribosome interactions are required for recruitment and activation.
• ZAK activation occurs via SAM domain dimerization at the ribosome collision site, involving RACK1.
• SERBP1 negatively regulates ZAK activation, preventing its constitutive activity.
• ZAK SAM domain variants influence kinase activity on and off the ribosome.

Conclusions:

• Provides a mechanistic blueprint for ZAK kinase activity at collided ribosomes.
• Highlights the role of ZAK-ribosome interactions in cellular stress response.
• Identifies SERBP1 as a key negative regulator of ZAK activation.