The MDMX Acidic Domain Uses Allovalency to Bind Both p53 and MDMX |
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| Affiliation: | 1. Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL 33620, United States;2. Molecular Oncology Department, Moffitt Cancer Center, Tampa, FL 33612, United States;1. Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, KS 66160, United States;2. Eye Research Institute, Oakland University, Rochester, MI 48309, United States;3. Department of Chemistry, Lehigh University, Bethlehem, PA 18015, United States;1. Institut de Biotecnologia i de Biomedicina (IBB) and Dept. de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain;2. Institut de Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBABS), Barcelona 08036, Spain;1. Bavarian NMR Center at the Department of Chemistry, Technical University of Munich, Ernst-Otto-Fischer Strasse 2, 85748 Garching, Germany;2. Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany;1. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA;2. Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy;3. Macromolecular Diffraction Facility, Cornell High Energy Synchrotron Source (MacCHESS), Cornell University, 161 Synchrotron Drive, Ithaca, NY 14853, USA;1. Departments of Biochemistry & Molecular Biology and Oncology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary AB T2N 4N1, Canada;2. Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC V8W 2Y2, Canada |
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| Abstract: | Autoinhibition of p53 binding to MDMX requires two short-linear motifs (SLiMs) containing adjacent tryptophan (WW) and tryptophan-phenylalanine (WF) residues. NMR spectroscopy was used to show the WW and WF motifs directly compete for the p53 binding site on MDMX and circular dichroism spectroscopy was used to show the WW motif becomes helical when it is bound to the p53 binding domain (p53BD) of MDMX. Binding studies using isothermal titration calorimetry showed the WW motif is a stronger inhibitor of p53 binding than the WF motif when they are both tethered to p53BD by the natural disordered linker. We also investigated how the WW and WF motifs interact with the DNA binding domain (DBD) of p53. Both motifs bind independently to similar sites on DBD that overlap the DNA binding site. Taken together our work defines a model for complex formation between MDMX and p53 where a pair of disordered SLiMs bind overlapping sites on both proteins. |
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| Keywords: | protein disorder p53 mimicry autoinhibition allovalency IDR" },{" #name" :" keyword" ," $" :{" id" :" k0035" }," $$" :[{" #name" :" text" ," _" :" Intrinsically Disordered Region AD" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" Acidic Domain DBD" },{" #name" :" keyword" ," $" :{" id" :" k0055" }," $$" :[{" #name" :" text" ," _" :" DNA Binding Domain TAD" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" Transactivation Domain p53BD" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" p53 Binding Domain SLiMs" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," _" :" Short Linear Motifs |
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