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      Mapping the native interaction surfaces of PREP1 with PBX1 by cross-linking mass-spectrometry and mutagenesis

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          Abstract

          Both onco-suppressor PREP1 and the oncogene MEIS1 bind to PBX1. This interaction stabilizes the two proteins and allows their translocation into the nucleus and thus their transcriptional activity. Here, we have combined cross-linking mass-spectrometry and systematic mutagenesis to detail the binding geometry of the PBX1-PREP1 (and PBX1-MEIS1) complexes, under native in vivo conditions. The data confirm the existence of two distinct interaction sites within the PBC domain of PBX1 and unravel differences among the highly similar binding sites of MEIS1 and PREP1. The HR2 domain has a fundamental role in binding the PBC-B domain of PBX1 in both PREP1 and MEIS1. The HR1 domain of MEIS1, however, seem to play a less stringent role in PBX1 interaction with respect to that of PREP1. This difference is also reflected by the different binding affinity of the two proteins to PBX1. Although partial, this analysis provides for the first time some ideas on the tertiary structure of the complexes not available before. Moreover, the extensive mutagenic analysis of PREP1 identifies the role of individual hydrophobic HR1 and HR2 residues, both in vitro and in vivo.

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          Modular Organization and Assembly of SWI/SNF Family Chromatin Remodeling Complexes

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              Cross-linking mass spectrometry: methods and applications in structural, molecular and systems biology

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                Author and article information

                Contributors
                chiara.bruckmann@ifom.eu
                francesco.blasi@ifom.eu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                8 October 2020
                8 October 2020
                2020
                : 10
                Affiliations
                [1 ]GRID grid.7678.e, ISNI 0000 0004 1757 7797, IFOM (Foundation FIRC Institute of Molecular Oncology), ; Via Adamello 16, 20139 Milan, Italy
                [2 ]GRID grid.429699.9, ISNI 0000 0004 1790 0507, Institute of Biostructures and Bioimaging (IBB)-CNR, ; Via Mezzocannone 16, 80134 Naples, Italy
                [3 ]GRID grid.15667.33, ISNI 0000 0004 1757 0843, Present Address: Department of Experimental Oncology, , European Institute of Oncology, ; Via Adamello 16, 20139 Milan, Italy
                [4 ]GRID grid.25786.3e, ISNI 0000 0004 1764 2907, Present Address: Center for Nanotechnology Innovation@NEST, , Istituto Italiano di Tecnologia, ; Piazza San Silvestro 12, 56124 Pisa, Italy
                [5 ]Present Address: Cogentech S.R.L. Benefit Corporation IT, Via Adamello 16, 20139 Milan, Italy
                Article
                74032
                10.1038/s41598-020-74032-w
                7545097
                33033354
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004710, Fondazione Umberto Veronesi;
                Funded by: Regione Campamia
                Funded by: FundRef http://dx.doi.org/10.13039/501100005010, Associazione Italiana per la Ricerca sul Cancro;
                Award ID: 2015-16759
                Categories
                Article
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                © The Author(s) 2020

                Uncategorized

                structural biology, biochemistry, developmental biology

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