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7nmz

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Structure of 14-3-3 eta in complex with Nedd4-2(335-455) containing two 14-3-3 binding motifs Ser342 and Ser448

Structural highlights

7nmz is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.303Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

1433F_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negatively regulates the kinase activity of PDPK1.^[1]

Publication Abstract from PubMed

Neural precursor cell expressed developmentally down-regulated 4 ligase (Nedd4-2) is an E3 ubiquitin ligase that targets proteins for ubiquitination and endocytosis, thereby regulating numerous ion channels, membrane receptors and tumor suppressors. Nedd4-2 activity is regulated by autoinhibition, calcium binding, oxidative stress, substrate binding, phosphorylation and 14-3-3 protein binding. However, the structural basis of 14-3-3-mediated Nedd4-2 regulation remains poorly understood. Here, we combined several techniques of integrative structural biology to characterize Nedd4-2 and its complex with 14-3-3. We demonstrate that phosphorylated Ser(342) and Ser(448) are the key residues that facilitate 14-3-3 protein binding to Nedd4-2 and that 14-3-3 protein binding induces a structural rearrangement of Nedd4-2 by inhibiting interactions between its structured domains. Overall, our findings provide the structural glimpse into the 14-3-3-mediated Nedd4-2 regulation and highlight the potential of the Nedd4-2:14-3-3 complex as a pharmacological target for Nedd4-2-associated diseases such as hypertension, epilepsy, kidney disease and cancer.

14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains.,Pohl P, Joshi R, Petrvalska O, Obsil T, Obsilova V Commun Biol. 2021 Jul 22;4(1):899. doi: 10.1038/s42003-021-02419-0. PMID:34294877^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sato S, Fujita N, Tsuruo T. Regulation of kinase activity of 3-phosphoinositide-dependent protein kinase-1 by binding to 14-3-3. J Biol Chem. 2002 Oct 18;277(42):39360-7. Epub 2002 Aug 12. PMID:12177059 doi:http://dx.doi.org/10.1074/jbc.M205141200
↑ Pohl P, Joshi R, Petrvalska O, Obsil T, Obsilova V. 14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains. Commun Biol. 2021 Jul 22;4(1):899. PMID:34294877 doi:10.1038/s42003-021-02419-0