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    Conformational Stability and Catalytic Activity of PTEN Variants Linked to Cancers and Autism Spectrum Disorders
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    † ‡ †Department of Biochemistry and ‡Department of Chemistry, University of Wisconsin—Madison, Madison, Wisconsin 53706, United States
    *E-mail: [email protected]
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    Biochemistry

    Cite this: Biochemistry 2015, 54, 7, 1576–1582
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    https://doi.org/10.1021/acs.biochem.5b00028
    Published February 3, 2015
    Copyright © 2015 American Chemical Society
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    Abstract

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    Phosphoinositides are membrane components that play critical regulatory roles in mammalian cells. The enzyme PTEN, which catalyzes the dephosphorylation of the phosphoinositide PIP3, is damaged in most sporadic tumors. Mutations in the PTEN gene have also been linked to autism spectrum disorders and other forms of delayed development. Here, human PTEN is shown to be on the cusp of unfolding under physiological conditions. Variants of human PTEN linked to somatic cancers and disorders on the autism spectrum are shown to be impaired in their conformational stability, catalytic activity, or both. Those variants linked only to autism have activity higher than the activity of those linked to cancers. PTEN-L, which is a secreted trans-active isoform, has conformational stability greater than that of the wild-type enzyme. These data indicate that PTEN is a fragile enzyme cast in a crucial role in cellular metabolism and suggest that PTEN-L is a repository for a critical catalytic activity.

    Copyright © 2015 American Chemical Society

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    This article is cited by 24 publications.

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    8. Payel Ganguly, Landiso Madonsela, Jesse T. Chao, Christopher J. R. Loewen, Timothy P. O’Connor, Esther M. Verheyen, Douglas W. Allan, . A scalable Drosophila assay for clinical interpretation of human PTEN variants in suppression of PI3K/AKT induced cellular proliferation. PLOS Genetics 2021, 17 (9) , e1009774. https://doi.org/10.1371/journal.pgen.1009774
    9. Ashitha S. Niranjana Murthy, Raviraj V. Suresh, Ramachandra Nallur B.. Comprehensive in silico mutational-sensitivity analysis of PTEN establishes signature regions implicated in pathogenesis of Autism Spectrum Disorders. Genomics 2021, 113 (1) , 999-1017. https://doi.org/10.1016/j.ygeno.2020.10.035
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    12. Michael Maglegaard Jepsen, Douglas M. Fowler, Rasmus Hartmann-Petersen, Amelie Stein, Kresten Lindorff-Larsen. Classifying disease-associated variants using measures of protein activity and stability. 2020, 91-107. https://doi.org/10.1016/B978-0-12-819132-3.00005-1
    13. Iris Nira Smith, Stetson Thacker, Ritika Jaini, Charis Eng. Dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes. Journal of Biomolecular Structure and Dynamics 2019, 37 (7) , 1766-1782. https://doi.org/10.1080/07391102.2018.1465854
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    16. Taylor L. Mighell, Sara Evans-Dutson, Brian J. O’Roak. A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships. The American Journal of Human Genetics 2018, 102 (5) , 943-955. https://doi.org/10.1016/j.ajhg.2018.03.018
    17. Prerna Malaney, Vladimir N. Uversky, Vrushank Davé. PTEN proteoforms in biology and disease. Cellular and Molecular Life Sciences 2017, 74 (15) , 2783-2794. https://doi.org/10.1007/s00018-017-2500-6
    18. Christina Gross. Defective phosphoinositide metabolism in autism. Journal of Neuroscience Research 2017, 95 (5) , 1161-1173. https://doi.org/10.1002/jnr.23797
    19. Hanadi Baeissa, Graeme Benstead-Hume, Christopher J. Richardson, Frances M.G. Pearl. Identification and analysis of mutational hotspots in oncogenes and tumour suppressors. Oncotarget 2017, 8 (13) , 21290-21304. https://doi.org/10.18632/oncotarget.15514
    20. Sean B. Johnston, Ronald T. Raines. PTENpred: A Designer Protein Impact Predictor for PTEN-related Disorders. Journal of Computational Biology 2016, 23 (12) , 969-975. https://doi.org/10.1089/cmb.2016.0058
    21. Yu-Chih Lin, Jeannine A. Frei, Michaela B. C. Kilander, Wenjuan Shen, Gene J. Blatt. A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons. Frontiers in Cellular Neuroscience 2016, 10 https://doi.org/10.3389/fncel.2016.00263
    22. Iris N. Smith, James M. Briggs. Structural mutation analysis of PTEN and its genotype‐phenotype correlations in endometriosis and cancer. Proteins: Structure, Function, and Bioinformatics 2016, 84 (11) , 1625-1643. https://doi.org/10.1002/prot.25105
    23. Ioanna Tzani, Ivaylo P. Ivanov, Dmitri E. Andreev, Ruslan I. Dmitriev, Kellie A. Dean, Pavel V. Baranov, John F. Atkins, Gary Loughran. Systematic analysis of the PTEN 5′ leader identifies a major AUU initiated proteoform. Open Biology 2016, 6 (5) , 150203. https://doi.org/10.1098/rsob.150203
    24. Hung-Chih Hsu, Tan Kien Thiam, Yen-Jung Lu, Chien Yuh Yeh, Wen-Sy Tsai, Jeng Fu You, Hsin Yuan Hung, Chi-Neu Tsai, An Hsu, Hua-Chien Chen, Shu-Jen Chen, Tsai-Sheng Yang. Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients. Oncotarget 2016, 7 (16) , 22257-22270. https://doi.org/10.18632/oncotarget.8076
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    Biochemistry

    Cite this: Biochemistry 2015, 54, 7, 1576–1582
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.biochem.5b00028
    Published February 3, 2015
    Copyright © 2015 American Chemical Society
    Request reuse permissions

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