Yu Jielin, Marintchev Assen
Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA, USA.
BMC Struct Biol. 2018 Sep 4;18(1):11. doi: 10.1186/s12900-018-0091-6.
Eukaryotic translation initiation factor 1A (eIF1A) is universally conserved in all organisms. It has multiple functions in translation initiation, including assembly of the ribosomal pre-initiation complexes, mRNA binding, scanning, and ribosomal subunit joining. eIF1A binds directly to the small ribosomal subunit, as well as to several other translation initiation factors. The structure of an eIF1A homolog, the eIF1A domain-containing protein (eIF1AD) was recently determined but its biological functions are unknown. Since eIF1AD has a known structure, as well as a homolog, whose structure and functions have been extensively studied, it is a very attractive target for sequence and structure analysis.
Structure/sequence analysis of eIF1AD found significant conservation in the surfaces corresponding to the ribosome-binding surfaces of its paralog eIF1A, including a nearly invariant surface-exposed tryptophan residue, which plays an important role in the interaction of eIF1A with the ribosome. These results indicate that eIF1AD may bind to the ribosome, similar to its paralog eIF1A, and could have roles in ribosome biogenenesis or regulation of translation. We identified conserved surfaces and sequence motifs in the folded domain as well as the C-terminal tail of eIF1AD, which are likely protein-protein interaction sites. The roles of these regions for eIF1AD function remain to be determined. We have also identified a set of trypanosomatid-specific surface determinants in eIF1A that could be a promising target for development of treatments against these parasites.
The results described here identify regions in eIF1A and eIF1AD that are likely to play major functional roles and are promising therapeutic targets. Our findings and hypotheses will promote new research and help elucidate the functions of eIF1AD.
真核生物翻译起始因子1A（eIF1A）在所有生物中普遍保守。它在翻译起始过程中具有多种功能，包括核糖体起始前复合物的组装、mRNA结合、扫描以及核糖体亚基的结合。eIF1A直接与小核糖体亚基以及其他几种翻译起始因子结合。最近确定了一种eIF1A同源物，即含eIF1A结构域的蛋白质（eIF1AD）的结构，但其生物学功能尚不清楚。由于eIF1AD具有已知结构以及一个同源物，其结构和功能已得到广泛研究，因此它是序列和结构分析的一个非常有吸引力的目标。
对eIF1AD的结构/序列分析发现，其与旁系同源物eIF1A的核糖体结合表面相对应的表面存在显著保守性，包括一个几乎不变的表面暴露色氨酸残基，该残基在eIF1A与核糖体的相互作用中起重要作用。这些结果表明，eIF1AD可能像其旁系同源物eIF1A一样与核糖体结合，并可能在核糖体生物发生或翻译调控中发挥作用。我们在eIF1AD的折叠结构域以及C末端尾巴中鉴定出保守表面和序列基序，它们可能是蛋白质-蛋白质相互作用位点。这些区域对eIF1AD功能的作用仍有待确定。我们还在eIF1A中鉴定出一组锥虫特异性表面决定簇，它们可能是开发针对这些寄生虫治疗方法的有前景的靶点。
本文所述结果确定了eIF1A和eIF1AD中可能发挥主要功能作用且是有前景的治疗靶点的区域。我们的发现和假设将促进新的研究，并有助于阐明eIF1AD的功能。
