title: Three Residues Make an Evolutionary Switch for Folding and RNA-Destabilizing Activity in the TTP Family of Proteins.
abstract: Tristetraprolin (TTP) binds to mRNA transcripts to promote their degradation. The TTP protein family in humans includes two other proteins, TIS11b and TIS11d. All three proteins contain a highly homologous RNA binding domain (RBD) that consists of two CCCH zinc fingers (ZFs). Both ZFs are folded in the absence of RNA in TIS11d and TIS11b. In TTP, however, only ZF1 adopts a stable fold. The focus of this study is to understand the origin and biological significance of the structural differences of the RBD. We identified three residues that affect the affinity for the structural Zn(2+) and determine the folding of ZF2 in the absence of RNA. We observed that the mRNA destabilizing activity of TTP was increased when the partially disordered RBD of TTP was replaced with the fully structured RBD of TIS11d, indicating that differences in the folded state of the RBD affect the activity of the proteins in the cell.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , 364 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Deveau
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , 364 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Francesca
authors.initials: F
authors.lastname: Massi
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D051816:Tristetraprolin / Q000737:chemistry* / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: D012333:RNA, Messenger; D014157:Transcription Factors; D051816:Tristetraprolin; C091750:ZFP36L2 protein, human; D015032:Zinc