WWP2: Difference between revisions

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</StructureSection>

== Function ==

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.

Studies suggest that the non-catalytic C2 domain and WW domains play a regulatory role in the catalytic activity of the HECT domain. Genetic deletions of WW domains and linkers have shown increased autoubiquitination activity. The WW domains and linkers play a role in altering protein conformation, with the 2,3-linker playing the greatest role.

This linker plays an autoinhibitory role. The ground state conformation of the protein has the 2,3-linker close to the N-lobe, while WW1 and WW2 domains block the N lobe’s ubiquitin-binding site. Upon phosphorylation the 2,3-linker changes conformation, moving further from the N lobe, allowing the protein to bind ubiquitin in the E2 and N lobe binding sites. This binding will further open the protein up to bind possible substrates, like PTEN.

Interactions between the hinge and the 2,3-linker appear to restrict flexibility of the C-lobe which is necessary for ubiquitin transferase activity. This interaction further locks the protein into the T position. A current model of WWP2 activation by Chen et. al. proposes the following: (1) autoinhibited WWP2 gets phosphorylated at the 2,3-linker, (2) loosening of the 2,3-linker interactions with the hinge and ubiquitin binding exosite allow ubiquitin to bind in the C-lobe, (3) the target substrate protein binds with specifity towards the WW domains, (4) the substrate protein gets ubiquitinated, and (5) the 2,3-linker gets dephosphorylated, allowing WWP2 to return to the autoinhibited ground state conformation.

== Relevance ==

Mutations in the NEDD4 family of proteins have been associated with several cancers and immune disorders. Many of these mutations occur in the 2,3-linker/HECT autoinhibited domains and the modified activity of the E3 Ligases as a result of these mutations can lead to an increase in the growth of tumor cells. WWP2 may play a role in the regulation of oncogenic signaling pathways through interactions with its substrate PTEN, a tumor suppressor in the PI3K pathway. The downregulation of voltage-gated sodium channels by WWP2 and other members of the NEDD4 family is an active area of research.

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@@ Line 19: / Line 19: @@
 </StructureSection>
 == Function ==
-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.
+Studies suggest that the non-catalytic C2 domain and WW domains play a regulatory role in the catalytic activity of the HECT domain. Genetic deletions of WW domains and linkers have shown increased autoubiquitination activity. The WW domains and linkers play a role in altering protein conformation, with the 2,3-linker playing the greatest role.
+This linker plays an autoinhibitory role. The ground state conformation of the protein has the 2,3-linker close to the N-lobe, while WW1 and WW2 domains block the N lobe’s ubiquitin-binding site. Upon phosphorylation the 2,3-linker changes conformation, moving further from the N lobe, allowing the protein to bind ubiquitin in the E2 and N lobe binding sites. This binding will further open the protein up to bind possible substrates, like PTEN.
+Interactions between the hinge and the 2,3-linker appear to restrict flexibility of the C-lobe which is necessary for ubiquitin transferase activity. This interaction further locks the protein into the T position. A current model of WWP2 activation by Chen et. al. proposes the following: (1) autoinhibited WWP2 gets phosphorylated at the 2,3-linker, (2) loosening of the 2,3-linker interactions with the hinge and ubiquitin binding exosite allow ubiquitin to bind in the C-lobe, (3) the target substrate protein binds with specifity towards the WW domains, (4) the substrate protein gets ubiquitinated, and (5) the 2,3-linker gets dephosphorylated, allowing WWP2 to return to the autoinhibited ground state conformation.
 == Relevance ==
+Mutations in the NEDD4 family of proteins have been associated with several cancers and immune disorders. Many of these mutations occur in the 2,3-linker/HECT autoinhibited domains and the modified activity of the E3 Ligases as a result of these mutations can lead to an increase in the growth of tumor cells. WWP2 may play a role in the regulation of oncogenic signaling pathways through interactions with its substrate PTEN, a tumor suppressor in the PI3K pathway. The downregulation of voltage-gated sodium channels by WWP2 and other members of the NEDD4 family is an active area of research.