title: MD and Docking Studies Reveal That the Functional Switch of CYFIP1 is Mediated by a Butterfly-like Motion.
abstract: Cytoplasmic FMRP interacting protein 1 (CYFIP1), also known as specifically RAC1 activated protein 1 (Sra1), plays a dual role: together with fragile X mental retardation protein (FMRP) and eIF4E it forms a complex that inhibits mRNA translation, while together with WAVE1, NCKAP1, ABI2, and HSPC300 it forms the WAVE regulatory complex (WRC) that upon RAC1 activation initiates actin polymerization. Here we performed a molecular dynamics (MD) simulation on CYFIP1 extracted from the known WRC structure, which shows that, in the absence of its WRC partners, a butterfly-like motion brings the two ends of CYFIP1 closer together, enabling the interaction with eIF4E. Our MD simulation is supported by available data showing that binding of CYFIP1 to eIF4E and binding to the WRC are mutually exclusive and that there is fluorescence resonance energy transfer between the N- and C-termini of CYFIP1. The differential interaction of RAC1-GTP with the two CYFIP1 structures predicts that RAC1 is directly responsible for the switch between these conformations.
authors.affiliation: VIB Center for the Biology of Disease, KU Leuven , 3000 Leuven, Belgium.|Center for Human Genetics, Leuven Research Institute for Neuroscience and Disease, KU Leuven , 3000 Leuven, Belgium.
authors.forename: Daniele
authors.initials: D
authors.lastname: Di Marino
authors.affiliation: SCAI SuperComputing Applications and Innovation Department, Cineca , Via dei Tizii 6, 00185 Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Chillemi
authors.affiliation: VIB Center for the Biology of Disease, KU Leuven , 3000 Leuven, Belgium.|Center for Human Genetics, Leuven Research Institute for Neuroscience and Disease, KU Leuven , 3000 Leuven, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: De Rubeis
authors.affiliation: Department of Physics, Sapienza University of Rome , 00185 Rome, Italy.|Center for Life Nano Science @Sapienza, Istituto Italiano di Tecnologia , P.le Aldo Moro 5, 00185 Rome, Italy.|Istituto Pasteur, Fondazione Cenci Bolognetti, Sapienza University , P.le Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Tramontano
authors.affiliation: VIB Center for the Biology of Disease, KU Leuven , 3000 Leuven, Belgium.|Center for Human Genetics, Leuven Research Institute for Neuroscience and Disease, KU Leuven , 3000 Leuven, Belgium.
authors.forename: Tilmann
authors.initials: T
authors.lastname: Achsel
authors.affiliation: VIB Center for the Biology of Disease, KU Leuven , 3000 Leuven, Belgium.|Center for Human Genetics, Leuven Research Institute for Neuroscience and Disease, KU Leuven , 3000 Leuven, Belgium.|Department of Biomedicine and Prevention, University of Rome "Tor Vergata" , 00133 Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bagni
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009068:Movement
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C109916:CYFIP1 protein, human