Alcalde-Rey Isabel, Velasco Beatriz Ramos, Alcalde José, Izquierdo José M
Centro de Biología Molecular Severo Ochoa (CBM), Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (CSIC/UAM), C/Nicolás Cabrera 1, 28049 Madrid, Spain.
Cells. 2024 Nov 27;13(23):1961. doi: 10.3390/cells13231961.
T-cell intracellular antigen 1 (TIA1) is an RNA-binding protein (RBP) that plays a multifunctional role in RNA metabolism. TIA1 has three RNA-Recognition Motifs (RRMs) and a prion-like carboxyl C-terminal domain (LCD) with intrinsically disordered regions (IDR) implicated in the dynamics (i.e., formation, assembly, and disassembly) of transient RNA-protein aggregates known as stress granules (SGs). A protein related to TIA1 is its paralog TIA1-related/like protein (TIAR/TIAL1), whose amino acid sequence, structural organisation, and molecular and cellular functions are highly conserved with TIA1. Both proteins are the main components of SGs, which are non-membranous RNA-protein condensates formed under stress to promote cell survival. Welander distal myopathy (WDM) is a late-onset muscular dystrophy that has been linked to a single-nucleotide substitution (c.1362G>A; p.E384K) in the gene encoding the TIA1 protein, which impacts TIA1-dependent SGs dynamics. Herein, we have analysed cellular and molecular aspects by targeting mutagenesis to position 384 to understand its molecular grammar in an amino acid/proteinogenic-dependent or -independent manner under oxidative stress. The observations suggest differential, even opposing, behaviours between TIA1 and TIAR in the presence of specific amino acids with negative and positive charges, and also uncharged acids, at equivalent positions of TIA1 and TIAR, respectively. Collectively, these findings illustrate a characteristic molecular grammar of TIAR- and TIA1-dependent SGs under oxidative conditions, suggesting a gain of versatility between two structurally and functionally highly conserved/related proteins.
T 细胞胞内抗原 1（TIA1）是一种 RNA 结合蛋白（RBP），在 RNA 代谢中发挥多功能作用。TIA1 有三个 RNA 识别基序（RRMs）和一个类似朊病毒的羧基末端结构域（LCD），其内在无序区域（IDR）与被称为应激颗粒（SGs）的瞬时 RNA-蛋白质聚集体的动态变化（即形成、组装和解聚）有关。与 TIA1 相关的一种蛋白质是其旁系同源物 TIA1 相关/类似蛋白（TIAR/TIAL1），其氨基酸序列、结构组织以及分子和细胞功能与 TIA1 高度保守。这两种蛋白质都是 SGs 的主要成分，SGs 是在应激条件下形成的非膜性 RNA-蛋白质凝聚物，以促进细胞存活。韦兰德远端肌病（WDM）是一种迟发性肌肉营养不良症，已与编码 TIA1 蛋白的基因中的单核苷酸取代（c.1362G>A；p.E384K）相关联，这会影响 TIA1 依赖性 SGs 的动态变化。在此，我们通过将诱变靶向到 384 位来分析细胞和分子方面，以了解其在氧化应激下以氨基酸/蛋白质生成依赖性或非依赖性方式的分子语法。观察结果表明，在 TIA1 和 TIAR 的等效位置分别存在带负电荷和正电荷的特定氨基酸以及不带电荷的酸时，TIA1 和 TIAR 之间存在差异甚至相反的行为。总体而言，这些发现说明了氧化条件下 TIAR 和 TIA1 依赖性 SGs 的特征性分子语法，表明两种结构和功能高度保守/相关的蛋白质之间的多功能性增加。
