title: Structural Basis of the Disorder in the Tandem Zinc Finger Domain of the RNA-Binding Protein Tristetraprolin.
abstract: Tristetraprolin (TTP) and TIS11d are two human RNA-binding proteins that belong to the CCCH-type tandem zinc finger family. In the RNA-free state, TIS11d coordinates a zinc ion in each of its two fingers, while TTP coordinates a single zinc ion with the N-terminal zinc finger. We have previously identified three residues, located in the C-terminal half of a short α-helix in the second zinc finger, that control how structured the RNA-binding domain is in these two proteins: Y151, L152, and Q153 in TTP and H201, T202, and I203 in TIS11d. Here, we have used molecular dynamics, NMR spectroscopy, and other biochemical methods to investigate the role of these three residues in the stability of the RNA-binding domain. We found that the intrahelical hydrogen bond formed by the T202 hydroxyl group in the C-terminal zinc finger of TIS11d is necessary to allow for π-π stacking between the side chains of a conserved phenylalanine and the zinc-coordinating histidine. We demonstrated that the lack of this hydrogen bond in TTP is responsible for the reduced zinc affinity of the C-terminal zinc finger.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , Worcester, Massachusetts 01605, United States.
authors.forename: Davide
authors.initials: D
authors.lastname: Tavella
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , Worcester, Massachusetts 01605, United States.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Deveau
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, Massachusetts 01605, United States.|Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School , Worcester, Massachusetts 01605, United States.
authors.forename: Troy W
authors.initials: TW
authors.lastname: Whitfield
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , Worcester, Massachusetts 01605, United States.
authors.forename: Francesca
authors.initials: F
authors.lastname: Massi
mesh_terms: D002942:Circular Dichroism; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D019906:Nuclear Magnetic Resonance, Biomolecular; D010649:Phenylalanine / Q000737:chemistry; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051816:Tristetraprolin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015032:Zinc / Q000737:chemistry; D016335:Zinc Fingers
chemical_list: D016601:RNA-Binding Proteins; D051816:Tristetraprolin; D010649:Phenylalanine; D006639:Histidine; D015032:Zinc