Structural Insight Into the SKP1-CUL1-FBXO3-RBX1 Complex

Area of Science:

• Structural Biology
• Molecular Biology
• Biochemistry

Background:

• The SCF (Skp1-Cul1-F-box) E3 ubiquitin ligase complex regulates protein degradation.
• FBXO3 is a substrate-recognition component of SCF complexes, but its integration and activation mechanisms within SCF^FBXO3 were unclear.

Purpose of the Study:

• To elucidate the structural basis of FBXO3 incorporation into the human SCF complex.
• To investigate the conformational states and activation mechanisms of SCF^FBXO3.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structure of human SCF^FBXO3 at 3.70 Å resolution.

Main Results:

• The cryo-EM structure revealed how FBXO3's F-box domain interacts with SKP1 and the N-terminal region of CUL1 through hydrophobic interactions.
• A weak cryo-EM map for RBX1 suggests an inactive, closed conformation of unmodified SCF^FBXO3.

Conclusions:

• The structure provides insights into the assembly of SCF^FBXO3.
• CUL1 neddylation is proposed to be essential for transitioning SCF^FBXO3 to an active conformation, enhancing its E3 ligase activity.