WWP2: Difference between revisions

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 studied protein modules, consisting of less than 40 amino acids, fold into three-stranded beta-sheets. They are characterized by two highly conserved <scene name='84/848928/Trpsinww2/1'>Trp residues</scene> positioned 20-22 amino acids apart and a high affinity for proline-rich motifs. Linkers of varying length and secondary structure connect the C2 domain to WW1, WW1 to WW2, WW2 to WW3, WW3 to WW4, and WW4 to the HECT domain. A chimeric <scene name='84/848928/Overallcolored/10'>structure</scene> of WWP2 consisting of the <scene name='84/848928/Ww2_domain/8'>WW2 domain</scene>, the WW2-WW3 linker (<scene name='84/848928/Linkeronly/1'>2,3-linker</scene>), and the HECT domain is shown on the right.  

The HECT domain is divided into two lobes (labeled N and C). The N-lobe (silver) serves as a binding site for the E2-ubiquitin complex and includes an exosite for non-covalent ubiquitin binding relevant to autoinhibition while the C-lobe (green) contains an active site with a catalytic Cys residue to which the substrate ubiquitin molecule can covalently attach. A <scene name='84/848928/Hinge_zoomed/6'>hinge</scene> (magenta) connects the N and C lobes of the HECT domain and allows for flexible movement of the lobes as ubiquitin is transferred from the E2-ubiquitin complex docked on the N-lobe to the ubiquitin binding site in the C-lobe. A transthiolation reaction in this active site results in a thioester bond between the ubiquitin and a Cys residue. The HECT domain is in an inverse T shape when inactive (autoinhibited) and takes on an L shape when active. WW2 interaction with HECT is mediated by the six C terminal residues.