Structural Basis for the Versatile and Methylation-Dependent Binding of CTCF to DNA

• Type of Material: Article
• Authors: Hideharu Hashimoto, Emory University; Dongxue Wang, Emory University; John Horton, Emory University; Xing Zhang, Emory University; Victor Corces, Emory University; Xiaodong Cheng, Emory University
• Language: English
• Date: 2017-06-01
• Publisher: CELL PRESS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molcel.2017.05.004
• Title of Journal or Parent Work: Molecular Cell
• Volume: 66
• Issue: 5
• Start Page: 711
• End Page: +
• Grant/Funding Information: This work was supported by a grant from the National Institutes of Health GM049245-23 to X.Z. and X.C.; The Department of Biochemistry of Emory University School of Medicine supported the use of SER-CAT beamlines.
• Keywords: CODE; Life Sciences & Biomedicine; CPG METHYLATION; SITES; LOCUS; CRYSTAL-STRUCTURE; COMPLEX; Science & Technology; Cell Biology; RECOGNITION; CHROMATIN; GENOME; ZINC FINGERS; Biochemistry & Molecular Biology
• Research Categories: Biology, General; Health Sciences, Oncology; Chemistry, Biochemistry

Abstract

The multidomain CCCTC-binding factor (CTCF), containing a tandem array of 11 zinc fingers (ZFs), modulates the three-dimensional organization of chromatin. We crystallized the human CTCF DNA-binding domain in complex with a known CTCF-binding site. While ZF2 does not make sequence-specific contacts, each finger of ZF3–7 contacts three bases of the 15-bp consensus sequence. Each conserved nucleotide makes base-specific hydrogen bonds with a particular residue. Most of the variable base pairs within the core sequence also engage in interactions with the protein. These interactions compensate for deviations from the consensus sequence, allowing CTCF to adapt to sequence variations. CTCF is sensitive to cytosine methylation at position 2, but insensitive at position 12 of the 15-bp core sequence. These differences can be rationalized structurally. Although included in crystallizations, ZF10 and ZF11 are not visible, while ZF8 and ZF9 span the backbone of the DNA duplex, conferring no sequence specificity but adding to overall binding stability.