三个残基构成了TTP蛋白家族中折叠和RNA去稳定活性的进化开关。
Three Residues Make an Evolutionary Switch for Folding and RNA-Destabilizing Activity in the TTP Family of Proteins.
作者信息
Deveau Laura M, Massi Francesca
机构信息
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , 364 Plantation Street, Worcester, Massachusetts 01605, United States.
出版信息
ACS Chem Biol. 2016 Feb 19;11(2):435-43. doi: 10.1021/acschembio.5b00639. Epub 2015 Dec 14.
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.
锌指蛋白Tristetraprolin（TTP）与信使核糖核酸（mRNA）转录本结合以促进其降解。人类的TTP蛋白家族还包括另外两种蛋白，即TIS11b和TIS11d。这三种蛋白均含有一个高度同源的RNA结合结构域（RBD），该结构域由两个CCCH型锌指（ZF）组成。在TIS11d和TIS11b中，两个锌指在没有RNA的情况下都会折叠。然而，在TTP中，只有锌指1（ZF1）会形成稳定的折叠结构。本研究的重点是了解RBD结构差异的起源及其生物学意义。我们鉴定出了三个影响对结构锌离子（Zn2+）亲和力的残基，并确定了在没有RNA的情况下ZF2的折叠情况。我们观察到，当TTP部分无序的RBD被TIS11d完全结构化的RBD取代时，TTP的mRNA去稳定活性增强，这表明RBD折叠状态的差异会影响细胞中蛋白质的活性。
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