WWP2: Difference between revisions

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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Hannah Campbell, Tihitina Y Aytenfisu, Sandra B. Gabelli, Michal Harel

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 ==Structure==
-<StructureSection load='5TJ7' size='350' side='right' caption="WWP2 Ubiquitin Ligase Chimeric 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." scene="84/848928/Overallcolored/7">
+<StructureSection load='5TJ7' size='350' side='right' caption="WWP2 Ubiquitin Ligase Chimeric 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." scene="84/848928/Overallcolored/11">
 [[Image:WWP2 Scheme from paper fig 1A top.png|300px|right|thumb| WWP2 Scheme without C2 Domain]]
 [[Image:WWP2 Scheme from paper D3.png|300px|right|thumb| 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 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.
+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/11'>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 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 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/7'>hinge</scene> 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.
-The alpha-helical 2,3-linker is subject to tyrosine phosphorylation at either end of the linker at residues <scene name='84/848928/Tyr392tyr369/1'>Tyr369 and Tyr392</scene>. Chen et. al. have shown that the phosphorylation of Tyr369 allows for allosteric activation by ubiquitination at the exosite in the N-lobe, while phosphorylation of Tyr392 residue leads to a destabilization of the T conformation of the HECT domain.
+The alpha-helical 2,3-linker is subject to tyrosine phosphorylation at either end of the linker at residues <scene name='84/848928/Tyr392tyr369/2'>Tyr369 and Tyr392</scene>. Chen et. al. have shown that the phosphorylation of Tyr369 allows for allosteric activation by ubiquitination at the exosite in the N-lobe, while phosphorylation of Tyr392 residue leads to a destabilization of the T conformation of the HECT domain.
 == Function ==