Fig. 2: Activation and autoinhibition of WWP1.
From: WWP1 E3 ligase at the crossroads of health and disease
A The cartoon depicts WWP1 E3 ligase transfers ubiquitin (Ub) molecules from E2 to E3, finally from E3 to its target substrates. Ub binds to catalytically active cysteine site of the E1 activating enzyme in an ATP-dependent manner. The E1 enzyme transfers the ubiquitin molecule to the catalytically active cysteine site of the E2 conjugating enzyme. E2 transfers the Ub molecule to the catalytically active cysteine site of E3 ubiquitin ligating enzyme by interacting with the N-terminus site of the WWP1 HECT domain. Finally, HECT domain transfers the Ub to the targeting substrate, which interacts with the WW domain of the WWP1. WWP1 directs different polyubiquitination linkages of its substrates: K27 polyubiquitination of PTEN and DVL2, K48 linkage of p27 and KLF5, K63-linked polyubiquitination of EGFR MUC1 etc. However, whether WWP1 directs polyubiquitination of its substrates through other linkages (K6, K11, K29 and K33) remains to be identified (denoted by a red question mark). B Wild-type WWP1 is autoinhibited through intramolecular interaction by sequestering its HECT domain in between the 2,3-linker and WW2-WW3 domains. C Mutations in the HECT domain disrupt the intramolecular autoinhibitory activity of WWP1 leading to its activation. D Intermolecular autoinhibition is carried out by the HECT domain of WWP1 which is sequestered in between the WW2 to WW3 linker domain. E The mutation in both the HECT domain inhibits the dimerization of WWP1.
