Viral Hijacking of Mitochondrial Lysyl-tRNA Synthetase

Kamińska, M.; Shalak, V. F.; Francin, Mathilde; Mirande, Marc

doi:10.1128/jvi.01267-06

Cited by 39 publications

(67 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings further define the composition of MSC, in which most components were proposed to have a stoichiometry of one per MSC (31,(43)(44)(45). Close inspection of the published work on previously purified MSCs, from various species, further indicates that, in many preparations, LysRS has twice the density expected for two LysRS molecules per MSC (24,31,46,47). Thus, the organization of the in vitro reconstructed complex reported here may reflect the native architectural arrangement of p38 and LysRS in the mammalian MSC.…”

Section: Discussionsupporting

confidence: 60%

Structural context for mobilization of a human tRNA synthetase from its cytoplasmic complex

Fang

Zhang

Shapiro

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Human lysyl-tRNA synthetase is bound to the multi-tRNA synthetase complex (MSC) that maintains and regulates the aminoacylation and nuclear functions of LysRS. The p38 scaffold protein binds LysRS to the MSC and, only with the appropriate cue, mobilizes LysRS for redirection to the nucleus to interact with the microphthalmia associated transcription factor (MITF). In recent work, an ðα 2 Þ 2 LysRS tetramer crystallized to yield a high-resolution structure and raised the question of how LysRS is arranged (dimer or tetramer) in the MSC to interact with p38. To understand the structural organization of the LysRS-p38 complex that regulates LysRS mobilization, we investigated the complex by use of small angle X-ray scattering and hydrogen-deuterium exchange with mass spectrometry in solution. The structure revealed a surprising α 2 β 1 ∶β 1 α 2 organization in which a dimeric p38 scaffold holds two LysRS α 2 dimers in a parallel configuration. Each of the N-terminal 48 residues of p38 binds one LysRS dimer and, in so doing, brings two copies of the LysRS dimer into the MSC. The results suggest that this unique geometry, which reconfigures the LysRS tetramer from α 2 ∶α 2 to α 2 β 1 ∶β 1 α 2 , is designed to control both retention and mobilization of LysRS from the MSC.noncanonical function | p38/AIMP2 | structural plasticity

show abstract

Section: Discussionsupporting

confidence: 60%

Structural context for mobilization of a human tRNA synthetase from its cytoplasmic complex

Fang

Zhang

Shapiro

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…One report suggests that the packaged viral LysRS is of host mitochondrial origin (17). However, earlier studies suggested that packaged LysRS does not appear to originate from any of its identified steady-state cellular compartments, which include the cytoplasmic MSC, nuclei, mitochondria, or cell membrane.…”

mentioning

confidence: 99%

Dual Role for Motif 1 Residues of Human Lysyl-tRNA Synthetase in Dimerization and Packaging into HIV-1

Dewan

Wei

Kleiman

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…However, the mitochondrial species of LysRS is the only species recovered in HIV-1 virions. 10 We tried to evaluate the relative strength of association of cLysRS, pmLysRS and its CAT domain with p38, Pol, p6 ⁎ or IN (Fig. 7b) by introducing the lacZ reporter gene into the two-hybrid assay.…”

Section: Do P38 and Pol Compete For Association With Lysrs?mentioning

confidence: 99%

“…9 As a consequence, the cytoplasmic (cLysRS) and premitochondrial (pmLysRS) LysRS, the mitochondrial species produced in the cytoplasm before maturation during mitochondrial transport, share 576 amino acid residues and display a cross immunological response. 10 The pmLysRS and cLysRS species have specific N-terminal polypeptide extensions of 49 and 21 amino acid residues, respectively. When monospecific antibodies directed to these specific sequences were used to identify the LysRS species packaged into the HIV-1 virions, only the mitochondrial enzyme was detected.…”

Section: Introductionmentioning

confidence: 99%

“…When monospecific antibodies directed to these specific sequences were used to identify the LysRS species packaged into the HIV-1 virions, only the mitochondrial enzyme was detected. 10 In human cells, cLysRS is one of the components of the multi-aminoacyl-tRNA synthetase complex (MARS). 11 By contrast, in the mitochondria, mLysRS does not associate into MARS because other components of this complex are strictly cytosolic proteins.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Association of Mitochondrial Lysyl-tRNA Synthetase with HIV-1 GagPol Involves Catalytic Domain of the Synthetase and Transframe and Integrase Domains of Pol

Kobbi

Octobre

Dias

et al. 2011

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

Cytosolic and mitochondrial lysyl-tRNA synthetases (LysRS) are encoded by a single gene and can be distinguished only according to their very N-terminal sequences. It was believed that cytosolic LysRS is packaged into HIV-1 virions via its association with Gag. Using monospecific antibodies, it was later shown that only the mitochondrial LysRS is taken up in viral particles along with tRNA(3)(Lys), the primer for reverse transcription of the HIV-1 genome. In this work, we re-analyzed the interaction between LysRS and GagPol to determine whether the particular N-terminal sequence of mitochondrial LysRS triggers a specific recognition with GagPol, or if differential routing of the two LysRS species in vivo could explain specific and exclusive packaging of the mitochondrial species. Here, we show that LysRS associates with the Pol domain of GagPol. More specifically, the transframe (TF or p6) and integrase (IN) domain proteins of Pol interact with the catalytic domain of LysRS. A model of the assembly of the LysRS-tRNA(3)(Lys)-GagPol packaging complex is proposed, which is consistent with the release of its different components after maturation of GagPol in the virions. The cytoplasmic and mitochondrial LysRS species share an identical catalytic domain. Accordingly, we found that both enzymes have the intrinsic capacity to bind to GagPol in vitro. In addition, both enzymes interact with p38 in vitro, the scaffold protein of the cytoplasmic multi-aminoacyl-tRNA synthetase complex, even though only the cytoplasmic species of LysRS is a bona fide component of this complex. These results suggest that the different LysRS species are strictly targeted in vivo, and open new perspectives for the search of a new class of inhibitors of the HIV-1 development cycle that would block the packaging of tRNA(3)(Lys) into viral particles.

show abstract

Viral Hijacking of Mitochondrial Lysyl-tRNA Synthetase

Cited by 39 publications

References 31 publications

Structural context for mobilization of a human tRNA synthetase from its cytoplasmic complex

Structural context for mobilization of a human tRNA synthetase from its cytoplasmic complex

Dual Role for Motif 1 Residues of Human Lysyl-tRNA Synthetase in Dimerization and Packaging into HIV-1

Association of Mitochondrial Lysyl-tRNA Synthetase with HIV-1 GagPol Involves Catalytic Domain of the Synthetase and Transframe and Integrase Domains of Pol

Contact Info

Product

Resources

About