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首页> 外文期刊>Molecular and Cellular Biology >La-Related Protein 4 Binds Poly(A), Interacts with the Poly(A)-Binding Protein MLLE Domain via a Variant PAM2w Motif, and Can Promote mRNA Stability
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La-Related Protein 4 Binds Poly(A), Interacts with the Poly(A)-Binding Protein MLLE Domain via a Variant PAM2w Motif, and Can Promote mRNA Stability

机译：La相关蛋白4结合Poly（A），通过变体PAM2w母体与Poly（A）结合蛋白MLLE结构域相互作用，并可以促进mRNA稳定性

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摘要

The conserved RNA binding protein La recognizes UUU-3′OH on its small nuclear RNA ligands and stabilizes them against 3′-end-mediated decay. We report that newly described La-related protein 4 (LARP4) is a factor that can bind poly(A) RNA and interact with poly(A) binding protein (PABP). Yeast two-hybrid analysis and reciprocal immunoprecipitations (IPs) from HeLa cells revealed that LARP4 interacts with RACK1, a 40S ribosome- and mRNA-associated protein. LARP4 cosediments with 40S ribosome subunits and polyribosomes, and its knockdown decreases translation. Mutagenesis of the RNA binding or PABP interaction motifs decrease LARP4 association with polysomes. Several translation and mRNA metabolism-related proteins use a PAM2 sequence containing a critical invariant phenylalanine to make direct contact with the MLLE domain of PABP, and their competition for the MLLE is thought to regulate mRNA homeostasis. Unlike all ～150 previously analyzed PAM2 sequences, LARP4 contains a variant PAM2 (PAM2w) with tryptophan in place of the phenylalanine. Binding and nuclear magnetic resonance (NMR) studies have shown that a peptide representing LARP4 PAM2w interacts with the MLLE of PABP within the affinity range measured for other PAM2 motif peptides. A cocrystal of PABC bound to LARP4 PAM2w shows tryptophan in the pocket in PABC-MLLE otherwise occupied by phenylalanine. We present evidence that LARP4 expression stimulates luciferase reporter activity by promoting mRNA stability, as shown by mRNA decay analysis of luciferase and cellular mRNAs. We propose that LARP4 activity is integrated with other PAM2 protein activities by PABP as part of mRNA homeostasis.
机译：保守的RNA结合蛋白La识别其小核RNA配体上的UUU-3'OH，并使它们稳定以抵抗3'-端介导的衰变。我们报告，新描述的La相关蛋白4（LARP4）是可以结合poly（A）RNA并与poly（A）结合蛋白（PABP）相互作用的因子。酵母双杂交分析和HeLa细胞的相互免疫沉淀（IP）显示LARP4与RACK1相互作用，RACK1是40S核糖体和mRNA的相关蛋白。 LARP4具有40S核糖体亚基和多核糖体，其敲低会降低翻译。 RNA结合或PABP相互作用基序的诱变降低了LARP4与多核糖体的结合。几种与翻译和mRNA代谢相关的蛋白质使用包含关键不变苯丙氨酸的PAM2序列与PABP的MLLE域直接接触，据认为它们与MLLE的竞争调节了mRNA的稳态。与以前分析的所有约150个PAM2序列不同，LARP4包含一个变体PAM2（PAM2w），其中色氨酸代替了苯丙氨酸。结合和核磁共振（NMR）研究表明，代表LARP4 PAM2w的肽与PABP的MLLE相互作用，该亲和力范围是针对其他PAM2基序肽测得的。与LARP4 PAM2w结合的PABC共晶体在PABC-MLLE的口袋中显示色氨酸，否则被苯丙氨酸占据。我们提供的证据表明LARP4表达通过促进mRNA稳定性来刺激荧光素酶报道分子的活性，如荧光素酶和细胞mRNA的mRNA衰减分析所示。我们建议LARP4活性与PABP整合为其他PAM2蛋白活性，作为mRNA体内平衡的一部分。

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