WWP2

From Proteopedia

Revision as of 20:40, 16 June 2020

WWP2 Overall

Thoughts & Notes

Should we link this page to 5tjq (2,3-linker)? It also has a proteopedia page.

Introduction

WWP2 is a type of ubiquitin protein ligase. More specifically, it is a member of the HECT (Homologous to the E6-AP Carboxyl Terminus) E3 Ligases class which accept a ubiquitin molecule from an enzyme upstream in the ubiquitination pathway and transfer the ubiquitin to a Lysine residue in the target signaling molecule or transcription factor. Ubiquitination can impact proteins in several different ways. Notably, it can serve as a signal for degradation, lead to translocation within the cell, and result in altered activity and altered protein-protein interactions. The thioester bond formation between an active site Cystine on HECT E3 Ligases and ubiquitin 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 (neuronal precursor cell-expressed developmentally down regulated 4) family which generally target proteins with a PPxY motif. NEDD4 E3 Ligases consist of an N-terminal C2 domain, between two and four WW domains, and a C-terminal HECT domain.

Structure

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 The of WWP2 consists of a C2 domain, four WW domains (labeled WW1-WW4), two lobes (labeled N and C), and a HECT domain. The active site Cystine? WWP2 has a (shown in red) that is alpha helical in shape and connects WW2 and WW2 domains. This 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. 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. WWP2 Scheme without C2 Domain WWP2 Scheme WW2-2,3-linker-HECT

Function

Disease

Relevance

Structural highlights

References

1. A Tunable Brake for HECT Ubiquitin Ligases.,Chen Z, Jiang H, Xu W, Li X, Dempsey DR, Zhang X, Devreotes P, Wolberger C, Amzel LM, Gabelli SB, Cole PA Mol Cell. 2017 May 4;66(3):345-357.e6. doi: 10.1016/j.molcel.2017.03.020. PMID:2847587