6ef4 | pdb_00006ef4

Crystal structure of mouse PP2A Aalpha P179R mutant

spinqualitylabelsall models 6ef4, resolution 3.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ef4 is a 1 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Gene: Ppp2r1a (LK3 transgenic mice) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [2AAA_MOUSE] The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. Required for proper chromosome segregation and for centromeric localization of SGOL1 in mitosis (By similarity). Publication Abstract from PubMed Somatic mutation of the PP2A Aalpha-subunit gene PPP2R1A is highly prevalent in high-grade endometrial carcinoma (EMCA). The structural, molecular, and biological basis by which the most recurrent EMCA-specific mutation site P179 facilitates features of EMCA malignancy have yet to be fully determined. Here we used a series of structural, biochemical, and biological approaches to investigate the impact of the P179R missense mutation on PP2A function. Enhanced sampling molecular dynamics simulations showed that arginine-to-proline substitution at the P179 residue changes the protein's stable conformation profile. A crystal structure of the tumor-derived PP2A mutant revealed marked changes in A-subunit conformation. Binding to the PP2A catalytic subunit was significantly impaired, disrupting holoenzyme formation and enzymatic activity. Cancer cells were dependent on PP2A disruption for sustained tumorigenic potential, and restoration of wildtype Aalpha in a patient-derived P179R mutant cell line restored enzyme function and significantly attenuated tumorigenesis and metastasis in vivo. Furthermore, small molecule-mediated therapeutic reactivation of PP2A significantly inhibited tumorigenicity in vivo. These outcomes implicate PP2A functional inactivation as a critical component of high-grade EMCA disease pathogenesis. Moreover, they highlight PP2A reactivation as a potential therapeutic strategy for patients who harbor P179R PPP2R1A mutations. The highly recurrent PP2A Aalpha-subunit mutation P179R alters protein structure and impairs PP2A enzyme function to promote endometrial tumorigenesis.,Taylor SE, O'Connor CM, Wang Z, Shen G, Song H, Leonard D, Sangodkar J, LaVasseur C, Avril S, Waggoner S, Zanotti K, Armstrong AJ, Nagel C, Resnick K, Singh S, Jackson MW, Xu W, Haider S, DiFeo A, Narla G Cancer Res. 2019 May 29. pii: 0008-5472.CAN-19-0218. doi:, 10.1158/0008-5472.CAN-19-0218. PMID:31142515 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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