دورية أكاديمية
Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme
| العنوان: | Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme |
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| المؤلفون: | Fedoryshchak, Roman O, Přechová, Magdalena, Butler, Abbey M, Lee, Rebecca, O'Reilly, Nicola, Flynn, Helen R, Snijders, Ambrosius P, Eder, Noreen, Ultanir, Sila, Mouilleron, Stephane, Treisman, Richard |
| المساهمون: | H2020 European Research Council, Cancer Research UK, Medical Research Council, Wellcome Trust |
| المصدر: | eLife ; volume 9 ; ISSN 2050-084X |
| بيانات النشر: | eLife Sciences Publications, Ltd |
| سنة النشر: | 2020 |
| المجموعة: | eLife (E-Journal - via CrossRef) |
| الوصف: | PPP-family phosphatases such as PP1 have little intrinsic specificity. Cofactors can target PP1 to substrates or subcellular locations, but it remains unclear how they might confer sequence-specificity on PP1. The cytoskeletal regulator Phactr1 is a neuronally enriched PP1 cofactor that is controlled by G-actin. Structural analysis showed that Phactr1 binding remodels PP1's hydrophobic groove, creating a new composite surface adjacent to the catalytic site. Using phosphoproteomics, we identified mouse fibroblast and neuronal Phactr1/PP1 substrates, which include cytoskeletal components and regulators. We determined high-resolution structures of Phactr1/PP1 bound to the dephosphorylated forms of its substrates IRSp53 and spectrin αII. Inversion of the phosphate in these holoenzyme-product complexes supports the proposed PPP-family catalytic mechanism. Substrate sequences C-terminal to the dephosphorylation site make intimate contacts with the composite Phactr1/PP1 surface, which are required for efficient dephosphorylation. Sequence specificity explains why Phactr1/PP1 exhibits orders-of-magnitude enhanced reactivity towards its substrates, compared to apo-PP1 or other PP1 holoenzymes. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.7554/elife.61509 |
| الإتاحة: | https://doi.org/10.7554/elife.61509Test https://cdn.elifesciences.org/articles/61509/elife-61509-v2.pdfTest https://cdn.elifesciences.org/articles/61509/elife-61509-v2.xmlTest https://elifesciences.org/articles/61509Test |
| حقوق: | http://creativecommons.org/licenses/by/4.0Test/ ; http://creativecommons.org/licenses/by/4.0Test/ ; http://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.8845E124 |
| قاعدة البيانات: | BASE |
| DOI: | 10.7554/elife.61509 |
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