6p6b: Difference between revisions

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'''Unreleased structure'''


The entry 6p6b is ON HOLD
==CS-Rosetta Model of PEA-15 Death Effector Domain==
<StructureSection load='6p6b' size='340' side='right'caption='[[6p6b]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6p6b]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P6B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6P6B FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6p6b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p6b OCA], [https://pdbe.org/6p6b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6p6b RCSB], [https://www.ebi.ac.uk/pdbsum/6p6b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6p6b ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PEA15_HUMAN PEA15_HUMAN] Blocks Ras-mediated inhibition of integrin activation and modulates the ERK MAP kinase cascade. Inhibits RPS6KA3 activities by retaining it in the cytoplasm (By similarity). Inhibits both TNFRSF6- and TNFRSF1A-mediated CASP8 activity and apoptosis. Regulates glucose transport by controlling both the content of SLC2A1 glucose transporters on the plasma membrane and the insulin-dependent trafficking of SLC2A4 from the cell interior to the surface.<ref>PMID:9670003</ref> <ref>PMID:10442631</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) exerts its regulatory roles on several critical cellular pathways through protein-protein interactions depending on its phosphorylation states. It can either inhibit the extracellular signal-regulated kinase (ERK) activities when it is dephosphorylated or block the assembly of death-inducing signaling complex (DISC) and the subsequent activation of apoptotic initiator, caspase-8, when it is phosphorylated. Due to the important roles of PEA-15 in regulating these pathways that lead to opposite cellular outcomes (cell proliferation vs. cell death), we proposed a phosphostasis (phosphorylation homeostasis) model, in which the phosphorylation states of the protein are vigorously controlled and regulated to maintain a delicate balance. The phosphostasis gives rise to the protective cellular functions of PEA-15 to preserve optimum cellular conditions. In this article, using advanced multidimensional nuclear magnetic resonance (NMR) techniques combined with a novel chemical shift (CS)-Rosetta algorithm for de novo protein structural determination, we report a novel conformation of PEA-15 death-effector domain (DED) upon interacting with ERK2. This new conformation is modulated by the irregularly structured C-terminal tail when it first recognizes and binds to ERK2 at the d-peptide recruitment site (DRS) in an allosteric manner, and is facilitated by the rearrangement of the surface electrostatic and hydrogen-bonding interactions on the DED. In this ERK2-bound conformation, three of the six helices (alpha2, alpha3, and alpha4) comprising the DED reorient substantially in comparison to the free-form structure, exposing key residues on the other three helices that directly interact with ERK2 at the DEF-docking site (docking site for ERK, FxF) and the activation loop. Additionally, we provide evidence that the phosphorylation of the C-terminal tail leads to a distinct conformation of DED, allowing efficient interactions with Fas-associated death domain (FADD) protein at the DISC. Our results substantiate the allosteric regulatory roles of the C-terminal tail in modulating DED conformation and facilitating protein-protein interactions of PEA-15.


Authors: Wei, Y., Crespo Flores, S., Cabezas, A., Hassan, S.
PEA-15 C-Terminal Tail Allosterically Modulates Death-Effector Domain Conformation and Facilitates Protein-Protein Interactions.,Crespo-Flores SL, Cabezas A, Hassan S, Wei Y Int J Mol Sci. 2019 Jul 7;20(13). pii: ijms20133335. doi: 10.3390/ijms20133335. PMID:31284641<ref>PMID:31284641</ref>


Description: CS-Rosetta Model of PEA-15 Death Effector Domain
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Hassan, S]]
<div class="pdbe-citations 6p6b" style="background-color:#fffaf0;"></div>
[[Category: Crespo Flores, S]]
== References ==
[[Category: Cabezas, A]]
<references/>
[[Category: Wei, Y]]
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cabezas A]]
[[Category: Crespo Flores S]]
[[Category: Hassan S]]
[[Category: Wei Y]]
Retrieved from "https://proteopedia.org/6p6b"