6dcx
From Proteopedia
iASPP-PP-1c structure and targeting of p53
Structural highlights
FunctionPP1A_HUMAN Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Regulates NEK2 function in terms of kinase activity and centrosome number and splitting, both in the presence and absence of radiation-induced DNA damage. Regulator of neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development.[1] Publication Abstract from PubMedASPP (apoptosis-stimulating proteins of p53) proteins bind PP-1c (protein phosphatase 1) and regulate p53 impacting cancer cell growth and apoptosis. Here we determine the crystal structure of the oncogenic ASPP protein, iASPP, bound to PP-1c. The structure reveals a 1:1 complex that relies on interactions of the iASPP SILK and RVxF motifs with PP-1c, plus interactions of the PP-1c PxxPxR motif with the iASPP SH3 domain. Small-angle X-ray scattering analyses suggest that the crystal structure undergoes slow interconversion with more extended conformations in solution. We show that iASPP, and the tumor suppressor ASPP2, enhance the catalytic activity of PP-1c against the small-molecule substrate, pNPP as well as p53. The combined results suggest that PxxPxR binding to iASPP SH3 domain is critical for complex formation, and that the modular ASPP-PP-1c interface provides dynamic flexibility that enables functional binding and dephosphorylation of p53 and other diverse protein substrates. Flexible Tethering of ASPP Proteins Facilitates PP-1c Catalysis.,Zhou Y, Millott R, Kim HJ, Peng S, Edwards RA, Skene-Arnold T, Hammel M, Lees-Miller SP, Tainer JA, Holmes CFB, Glover JNM Structure. 2019 Oct 1;27(10):1485-1496.e4. doi: 10.1016/j.str.2019.07.012. Epub, 2019 Aug 8. PMID:31402222[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found See AlsoReferences
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