title: The Mutational Landscape of the Oncogenic MZF1 SCAN Domain in Cancer.
abstract: SCAN domains in zinc-finger transcription factors are crucial mediators of protein-protein interactions. Up to 240 SCAN-domain encoding genes have been identified throughout the human genome. These include cancer-related genes, such as the myeloid zinc finger 1 (MZF1), an oncogenic transcription factor involved in the progression of many solid cancers. The mechanisms by which SCAN homo- and heterodimers assemble and how they alter the transcriptional activity of zinc-finger transcription factors in cancer and other diseases remain to be investigated. Here, we provide the first description of the conformational ensemble of the MZF1 SCAN domain cross-validated against NMR experimental data, which are probes of structure and dynamics on different timescales. We investigated the protein-protein interaction network of MZF1 and how it is perturbed in different cancer types by the analyses of high-throughput proteomics and RNASeq data. Collectively, we integrated many computational approaches, ranging from simple empirical energy functions to all-atom microsecond molecular dynamics simulations and network analyses to unravel the effects of cancer-related substitutions in relation to MZF1 structure and interactions.
authors.affiliation: Computational Biology Laboratory and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Nygaard
authors.affiliation: Computational Biology Laboratory and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
authors.forename: Thilde
authors.initials: T
authors.lastname: Terkelsen
authors.affiliation: Computational Biology Laboratory and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
authors.forename: André
authors.initials: A
authors.lastname: Vidas Olsen
authors.affiliation: Computational Biology Laboratory and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sora
authors.affiliation: Computational Biology Laboratory and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
authors.forename: Juan
authors.initials: J
authors.lastname: Salamanca Viloria
authors.affiliation: Department of Biomedical Sciences, University of Padua Padua, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Rizza
authors.affiliation: Computational Biology Laboratory and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
authors.forename: Sanne
authors.initials: S
authors.lastname: Bergstrand-Poulsen
authors.affiliation: Computational Biology Laboratory and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
authors.forename: Miriam
authors.initials: M
authors.lastname: Di Marco
authors.affiliation: Cell Stress and Survival Unit and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Vistesen
authors.affiliation: Department of Chemistry and Biochemistry, School of Biological and Chemical Sciences, Queen Mary University of London London, UK.
authors.forename: Matteo
authors.initials: M
authors.lastname: Tiberti
authors.affiliation: Computational Biology Laboratory and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
authors.forename: Matteo
authors.initials: M
authors.lastname: Lambrughi
authors.affiliation: Unit of Cell Death and Metabolism and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättelä
authors.affiliation: Unit of Cell Death and Metabolism and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
authors.forename: Tuula
authors.initials: T
authors.lastname: Kallunki
authors.affiliation: Computational Biology Laboratory and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
authors.forename: Elena
authors.initials: E
authors.lastname: Papaleo
keywords: FoldX; RNAseq; TCGA; cancer mutations; molecular dynamics; protein structure network; saturation mutagenesis; transcription factors