title: Deconvolving the recognition of DNA shape from sequence.
abstract: Protein-DNA binding is mediated by the recognition of the chemical signatures of the DNA bases and the 3D shape of the DNA molecule. Because DNA shape is a consequence of sequence, it is difficult to dissociate these modes of recognition. Here, we tease them apart in the context of Hox-DNA binding by mutating residues that, in a co-crystal structure, only recognize DNA shape. Complexes made with these mutants lose the preference to bind sequences with specific DNA shape features. Introducing shape-recognizing residues from one Hox protein to another swapped binding specificities in vitro and gene regulation in vivo. Statistical machine learning revealed that the accuracy of binding specificity predictions improves by adding shape features to a model that only depends on sequence, and feature selection identified shape features important for recognition. Thus, shape readout is a direct and independent component of binding site selection by Hox proteins.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Namiko
authors.initials: N
authors.lastname: Abe
authors.affiliation: Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA; Department of Biology, Technion - Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Dror
authors.affiliation: Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Slattery
authors.affiliation: Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Tianyin
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10032, USA.
authors.forename: Harmen J
authors.initials: HJ
authors.lastname: Bussemaker
authors.affiliation: Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA; Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA; Department of Physics and Astronomy, University of Southern California, Los Angeles, CA 90089, USA; Department of Computer Science, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: rohs@usc.edu.
authors.forename: Remo
authors.initials: R
authors.lastname: Rohs
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA. Electronic address: rsm10@columbia.edu.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Mann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D016415:Sequence Alignment; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D018398:Homeodomain Proteins; C059627:Scr protein, Drosophila; D014157:Transcription Factors; C083405:exd protein, Drosophila; D004247:DNA
references.citation: Nat Biotechnol. 2013 Feb;31(2):126-34
references.pmid: 23354101
references.citation: Cell. 2013 Jan 17;152(1-2):327-39
references.pmid: 23332764
references.citation: Cell Rep. 2013 Apr 25;3(4):1117-27
references.pmid: 23545501
references.citation: Cell Rep. 2013 Apr 25;3(4):1093-104
references.pmid: 23562153
references.citation: Nucleic Acids Res. 2013 Jul;41(Web Server issue):W56-62
references.pmid: 23703209
references.citation: Nucleic Acids Res. 2014 Jan;42(1):430-41
references.pmid: 24078250
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D148-55
references.pmid: 24214955
references.citation: Mol Cell. 2014 Jun 5;54(5):844-57
references.pmid: 24813947
references.citation: Methods Mol Biol. 2014;1196:255-78
references.pmid: 25151169
references.citation: Trends Biochem Sci. 2014 Sep;39(9):381-99
references.pmid: 25129887
references.citation: Nucleic Acids Res. 2015 Jan;43(Database issue):D117-22
references.pmid: 25378322
references.citation: Cell. 2015 Jan 15;160(1-2):191-203
references.pmid: 25557079
references.citation: Proc Natl Acad Sci U S A. 1976 Mar;73(3):804-8
references.pmid: 1062791
references.citation: Genes Dev. 1997 May 15;11(10):1327-40
references.pmid: 9171376
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11163-8
references.pmid: 9736707
references.citation: Genes Dev. 1999 Jul 1;13(13):1704-16
references.pmid: 10398683
references.citation: Genes Dev. 2006 Jun 15;20(12):1636-50
references.pmid: 16778079
references.citation: Cell. 2007 Nov 2;131(3):530-43
references.pmid: 17981120
references.citation: Science. 2009 Apr 17;324(5925):407-10
references.pmid: 19372434
references.citation: Curr Opin Struct Biol. 2009 Apr;19(2):171-7
references.pmid: 19362815
references.citation: Curr Top Dev Biol. 2009;88:63-101
references.pmid: 19651302
references.citation: Nature. 2009 Oct 29;461(7268):1248-53
references.pmid: 19865164
references.citation: Nat Struct Mol Biol. 2010 Apr;17(4):423-9
references.pmid: 20364130
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D111-7
references.pmid: 21097781
references.citation: Nucleic Acids Res. 2011 Jan;39(2):e6
references.pmid: 21051340
references.citation: Cell. 2011 Dec 9;147(6):1270-82
references.pmid: 22153072
references.citation: Nucleic Acids Res. 2012 Aug;40(14):e106
references.pmid: 22492513
references.citation: Nucleic Acids Res. 2012 Dec;40(22):e175
references.pmid: 22923524
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6376-81
references.pmid: 23576721