FAF1 and FAF2 enhance unfolding by p97-UFD1-NPL4 complex enabling rational design of p97 activators.

FAF1 and FAF2 significantly boost p97-UFD1-NPL4 complex activity, increasing substrate unfolding efficiency by engaging key cofactors and conserved activation motifs.

• Why it matters: Understanding how cofactors modulate p97 activity is crucial for deciphering cellular protein quality control and developing targeted therapies for related diseases.
• What they did: Researchers screened cofactors and identified FAF2, then used biochemical and structural methods to reveal how FAF2 interacts with p97-UN and ubiquitin, defining a conserved activation motif.
• The result: This work enables the engineering of potent p97 activators, offering a strategic approach to enhance substrate unfolding and potentially treat conditions involving protein misfolding.