2nsz

From Proteopedia

1.15 Angstrom Crystal Structure of the MA3 domain of Pdcd4

PDB ID 2nsz

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Structural highlights

2nsz is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.15Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PDCD4_MOUSE Note=Decreases benign tumor development and malignant progression.

Function

PDCD4_MOUSE Inhibits translation initiation and cap-dependent translation. May excert its function by hindering the interaction between EIF4A1 and EIF4G. Inhibits the helicase activity of EIF4A. Modulates the activation of JUN kinase. Down-regulates the expression of MAP4K1, thus inhibiting events important in driving invasion, namely, MAPK85 activation and consequent JUN-dependent transcription. May play a role in apoptosis. Tumor suppressor. Inhibits tumor promoter-induced neoplastic transformation. Binds RNA.^[1] ^[2] ^[3] ^[4]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The tumor suppressor function of Programmed Cell Death 4 (Pdcd4) is achieved through interactions between Pdcd4 and components of the translation initiation complex, namely, the RNA helicase eIF4A and the scaffolding protein eIF4G. These interactions are mediated through two MA3 domains on the Pdcd4 molecule and result in inhibition of protein synthesis. We have solved the high-resolution crystal structure of the C-terminal MA3 (cMA3) domain of Pdcd4 in several crystal forms and demonstrated its similarity to the MA3 domain of eIF4G. As predicted by the structure, the cMA3 domain competes with eIF4Gc for binding to eIF4A and surprisingly is sufficient to inhibit translation initiation. Mutations that abolish eIF4A binding negate both functions of the cMA3. Interestingly mutations in the Akt phosphorylation site influenced neither cMA3 binding to eIF4A nor its ability to inhibit translation initiation. Finally, our structural analysis reveals MA3 domains to be a novel subfamily of VHS domains.

Structural basis for inhibition of translation by the tumor suppressor Pdcd4.,LaRonde-LeBlanc N, Santhanam AN, Baker AR, Wlodawer A, Colburn NH Mol Cell Biol. 2007 Jan;27(1):147-56. Epub 2006 Oct 23. PMID:17060447^[5]

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

References

↑ Yang HS, Jansen AP, Komar AA, Zheng X, Merrick WC, Costes S, Lockett SJ, Sonenberg N, Colburn NH. The transformation suppressor Pdcd4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation. Mol Cell Biol. 2003 Jan;23(1):26-37. PMID:12482958
↑ Bohm M, Sawicka K, Siebrasse JP, Brehmer-Fastnacht A, Peters R, Klempnauer KH. The transformation suppressor protein Pdcd4 shuttles between nucleus and cytoplasm and binds RNA. Oncogene. 2003 Jul 31;22(31):4905-10. PMID:12894233 doi:10.1038/sj.onc.1206710
↑ Jansen AP, Camalier CE, Colburn NH. Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis. Cancer Res. 2005 Jul 15;65(14):6034-41. PMID:16024603 doi:65/14/6034
↑ LaRonde-LeBlanc N, Santhanam AN, Baker AR, Wlodawer A, Colburn NH. Structural basis for inhibition of translation by the tumor suppressor Pdcd4. Mol Cell Biol. 2007 Jan;27(1):147-56. Epub 2006 Oct 23. PMID:17060447 doi:10.1128/MCB.00867-06
↑ LaRonde-LeBlanc N, Santhanam AN, Baker AR, Wlodawer A, Colburn NH. Structural basis for inhibition of translation by the tumor suppressor Pdcd4. Mol Cell Biol. 2007 Jan;27(1):147-56. Epub 2006 Oct 23. PMID:17060447 doi:10.1128/MCB.00867-06