1H, 13C and 15N resonance assignment of the N-terminal domain of human lysyl aminoacyl tRNA synthetase

Liu, Sheng; Decker, Aaron; Howell, Mike; Caperelli, Carol A.; Tsang, Pearl

doi:10.1007/s12104-012-9430-x

Cited by 6 publications

(15 citation statements)

References 18 publications

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“…The U-rich anticodon of tRNA Lys specifically interacts with the anticodon-binding domain (ACB) of human LysRS (Stello et al 1999). In contrast, interactions with a eukaryote-specific N-terminal extension domain of hLysRS are not believed to contribute to specific tRNA recognition, but increase overall tRNA binding affinity (Francin and Mirande 2006;Francin et al 2002;Liu et al 2013; S Liu, A Decker, M Refaei, P Tsang, C Jones, R Comandur, K Musier-Forsyth, J Hinerman, and A Herr, in prep. ).…”

Section: Introductionmentioning

confidence: 99%

Anticodon-like binding of the HIV-1 tRNA-like element to human lysyl-tRNA synthetase

Liu

Comandur

Jones

et al. 2016

RNA

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A critical step in the HIV-1 lifecycle involves reverse transcription of the viral genomic RNA (gRNA). Human tRNA Lys3 serves as a primer for transcription initiation and is selectively enriched in virus particles. Human lysyl-tRNA synthetase (hLysRS) is also packaged into virions. Recently, a tRNA-like element (TLE) within the HIV-1 gRNA was shown to mimic the global tRNA fold and bind competitively to hLysRS, suggesting a mechanism of tRNA targeting to the primer binding site (PBS) and release from the synthetase. Here, we use NMR to investigate hLysRS anticodon-binding domain (ACB) binding to six RNA oligonucleotides, including a hairpin derived from the HIV-1 gRNA TLE. We show that ACB interacts with submicromolar affinity to U-rich RNA oligonucleotides-the tRNA Lys3 anticodon stem-loop (ACSL), the WT TLE, and a nonanucleotide, U9. In contrast, the ACB bound only weakly to two TLE loop mutants and a C9 nonanucleotide. NMR chemical shift perturbations induced by each RNA indicate that the ACSL and the WT TLE both interact with the ACB in a strikingly similar manner. Taken together, these findings support the conclusion that tRNA mimicry by the HIV-1 genome leads to a highly specific protein-RNA interaction that facilitates efficient primer release from hLysRS prior to reverse transcription.

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Section: Introductionmentioning

confidence: 99%

Anticodon-like binding of the HIV-1 tRNA-like element to human lysyl-tRNA synthetase

Liu

Comandur

Jones

et al. 2016

RNA

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“…The extensions, as suggested by structural prediction, contain a long helix of 20–40 aa (Figure 3). The helical conformation was confirmed by NMR structure determination of the N-terminal extensions of human AspRS and human LysRS [3, 4]. …”

Section: Stepwise Appearance Of New Domains and Sequences In Highermentioning

confidence: 99%

Architecture and Metamorphosis

Guo

Yang

2013

Topics in Current Chemistry

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When compared to other conserved housekeeping protein families, such as ribosomal proteins, during the evolution of higher eukaryotes, aminoacyl-tRNA synthetases (aaRSs) show an apparent high propensity to add new sequences, and especially, new domains. The stepwise emergence of those new domains is consistent with their involvement in a broad range of biological functions beyond protein synthesis, and correlates with the increasing biological complexity of higher organisms. The new domains have been extensively characterized based on their evolutionary origins and their sequence, structural and functional features. While some of the domains are uniquely found in aaRSs and may have originated from nucleic acid binding motifs, others are common domain modules mediating protein-protein interactions that play a critical role in the assembly of the multi-synthetase complex (MSC). Interestingly, the MSC has emerged from a miniature complex in yeast, to a large, stable complex in insects to humans. The human MSC consists of 9 aaRSs (LysRS, ArgRS, GlnRS, AspRS, MetRS, IleRS, LeuRS and GluProRS) and 3 scaffold proteins (AIMP1/p43, AIMP2/p38 and AIMP3/p18), and has a molecular weight of 1.5 million Da. The MSC has been proposed to have a functional dualism: both facilitating protein synthesis and serving as a reservoir of non-canonical functions associated with its synthetase and non-synthetase components. Importantly, domain additions and functional expansions are not limited to the components of the MSC and are found in almost all aaRS proteins. From a structural perspective, multi-functionalities are represented by multiple conformational states. In fact, alternative conformations of aaRSs have been generated by various mechanisms from proteolysis to alternative splicing and posttranslational modifications, as well as by disease-causing mutations. Therefore, the metamorphosis between different conformational states is connected to the activation and regulation of the novel functions of aaRSs in higher eukaryotes.

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“…Human LysRS contains a eukaryote-specific N-terminal extension. NMR studies in solution revealed that the extension is mostly unstructured (Liu, et al, 2012). Consistently, LysRS can be crystallized only when this extension was removed (Guo, et al, 2008).…”

Section: New Domains Are Often Associated With or Near Structural Dismentioning

confidence: 99%

“…Interaction with a disordered partner has the advantage of high specificity that is rendered by the induced-fit mechanism. For example, tRNA interaction induces part of the N-terminal extension of LysRS (S19-E45) to adopt a helical structure that aligns positively charged residues on one side of the helix to enhance the specificity (Guo, et al, 2010; Liu, et al, 2012). …”

Section: Functional Significance Of Structural Disorders In Aarssmentioning

confidence: 99%

Structural Disorder in Expanding the Functionome of Aminoacyl-tRNA Synthetases

Yang

2013

Chemistry & Biology

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Over the last decade, aminoacyl-tRNA synthetases (AARSs) have emerged as a new class of regulatory proteins with widespread functions beyond their classic role in protein synthesis. The functional expansion concurs with the incorporation of new domains and motifs to AARSs and coincides with the emergence of the multi-synthetase complex (MSC) during the course of eukaryotic evolution. Notably, the new domains in AARSs are often found to be structurally disordered or to be linked to the enzyme cores via unstructured linkers. Further bioinformatic analysis performed here classifies the 20 human cytoplasmic AARSs into 3 groups based on their propensities for structural disorder. The analysis also suggests that, while the assembly of the MSC mainly involves ordered structural domains, structurally disordered regions play an important role in activating and expanding the regulatory functions of AARSs.

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1H, 13C and 15N resonance assignment of the N-terminal domain of human lysyl aminoacyl tRNA synthetase

Cited by 6 publications

References 18 publications

Anticodon-like binding of the HIV-1 tRNA-like element to human lysyl-tRNA synthetase

Anticodon-like binding of the HIV-1 tRNA-like element to human lysyl-tRNA synthetase

Architecture and Metamorphosis

Structural Disorder in Expanding the Functionome of Aminoacyl-tRNA Synthetases

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