WWP2

WWP2 Overall

Thoughts & NotesThoughts & Notes

5tjq (2,3-linker) proteopedia page place to input

IntroductionIntroduction

WWP2 (WW domain-containing protein 2) is a type of ubiquitin protein ligase. Ubiquitination can serve as a signal for degradation, lead to translocation within the cell, and result in altered activity and altered protein-protein interactions. The ubiquitination pathway comprises of ubiquitin-activating (E1), ubiquitin-conjugating (E2) and ubiquitin-ligating (E3) enzymes. WWP2 is a member of the HECT (Homologous to the E6-AP Carboxyl Terminus) E3 Ligases class of enzymes. HECT E3 Ligases accept a ubiquitin molecule from E2 enzymes and transfer the ubiquitin to a Lysine residue in the target signaling molecule or transcription factor. The thioester bond formation between an active site Cystine on HECT E3 Ligases and the ubiquitin ligand differentiates the HECT family of enzymes from the more abundant RING (Really Interacting New Gene) family of ubiquitin ligases which mediate ubiquitin transfer through non-covalent interactions. Within HECT E3 Ligases, WWP2 falls into the NEDD 4 family (named after the instance in which the first member was discovered: a study of developmentally down-regulated proteins in neuronal embryonic mouse cells) which generally target proteins with a PPxY motif. NEDD4 E3 Ligases consist of an amino-terminal C2 domain, between two and four WW domains, and a carboxy-terminal HECT domain.

StructureStructure

WWP2 Scheme without C2 Domain WWP2 Scheme WW2-2,3-linker-HECT Full-length WWP2 consists of an amino terminal C2 domain, four WW domains (labeled WW1-WW4) and a carboxy terminal HECT domain. WW domains are one of the smallest protein modules, consisting of less than 40 amino acids, and are characterized by two highly conserved 20-22 residues apart along with high affinity for proline-rich motifs. Linkers of varying length connect the C2 domain to WW1, WW1 to WW2, WW2 to WW3, WW3 to WW4, and WW4 to the HECT domain. A chimeric of WWP2 consisting of the WW2 domain, the WW2-WW3 linker (2,3-linker), and the HECT domain is shown on the right. The is alpha helical in shape. The domain is a 3 stranded beta sheet. The HECT domain is divided into two lobes (labeled N and C). There is a that connects the N and C lobes or this protein. This hinge also interacts with the 2,3-linker. The WW2 domain is a 3 stranded beta sheet. The HECT domain is in an inverse T shape when inactive and takes on an L shape when active. WW2 interaction with HECT is mediated by the six C terminal residues.

spinqualitylabelsall models WWP2 Ubiquitin Ligase Truncated Structure (PDB entry 5TJ7). The 2,3-linker (red) connects the WW2 domain (yellow) to the WW3 domain. A hinge connects the C-terminal lobe (green) and N-terminal lobe (silver) of the HECT domain. Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

FunctionFunction

The 2,3-linker plays an autoinhibitory role. Upon phosphorylation the 2,3-linker changes conformation, allowing the protein to bind ubiquitin in the E2 binding site. This binding will further open the protein up to bind possible substrates.

ReferencesReferences

1. Chen, Z., Jiang, H., Xu, W., Li, X., Dempsey, D. R., Zhang, X., . . . Cole, P. A. (2017). A Tunable Brake for HECT Ubiquitin Ligases. Molecular Cell, 66(3), 345-357. doi:10.1016/j.molcel.2017.03.020 PMID:28475870

2. Ingham, R.J., Gish, G., & Pawson, T.(2004) The Nedd4 family of E3 ubiquitin ligases: Functional diversity within a common modular architecture. Oncogene, 23(11), 1972-1984. doi:10.1038/sj.onc.1207436