WWP1: a versatile ubiquitin E3 ligase in signaling and diseases

Abstract

WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is a multifunction protein containing an N-terminal C2 domain, four tandem WW domains for substrate binding, and a C-terminal catalytic HECT domain for ubiquitin transferring. WWP1 has been suggested to function as the E3 ligase for several PY motif-containing proteins, such as Smad2, KLF5, p63, ErbB4/HER4, RUNX2, JunB, RNF11, SPG20, and Gag, as well as several non-PY motif containing proteins, such as TβR1, Smad4, KLF2, and EPS15. WWP1 regulates a variety of cellular biological processes including protein trafficking and degradation, signaling, transcription, and viral budding. WWP1 has been implicated in several diseases, such as cancers, infectious diseases, neurological diseases, and aging. In this review article, we extensively summarize the current knowledge of WWP1 with special emphasis on the roles and action of mechanism of WWP1 in signaling and human diseases.

Fig. 1

a The diagram of the WWP1 protein domains. The WWP1 protein contains 922 amino acid residues. The C2 domain at N-terminus is responsible for membrane and protein binding. The four WW domains in the central region are responsible for the interaction with substrate proteins. The WW1 and WW3 are type I WW domains that recognize PY motifs. The HECT domain at the C-terminus is responsible for the ubiquitin–protein ligase activity. The Cystein-890 is the catalytic activation site. b WWP1 regulates different substrates in different cellular processes