scholarly journals Critical Role of Helix 4 of HIV-1 Capsid C-terminal Domain in Interactions with Human Lysyl-tRNA Synthetase

2007 ◽  
Vol 282 (44) ◽  
pp. 32274-32279 ◽  
Author(s):  
Brandie J. Kovaleski ◽  
Robert Kennedy ◽  
Ahmad Khorchid ◽  
Lawrence Kleiman ◽  
Hiroshi Matsuo ◽  
...  
Keyword(s):  
Critical Role ◽  
Trna Synthetase ◽  
Terminal Domain ◽  
Hiv 1

scholarly journals The HIV-1 Integrase C-Terminal domain induces TAR RNA structural changes promoting Tat binding.

2021 ◽  
Author(s):  
Cecilia Rocchi ◽  
Camille Louvat ◽  
Adriana Erica Miele ◽  
Julien Batisse ◽  
Christophe Guillon ◽  
...  
Keyword(s):  
Viral Particle ◽  
Structural Changes ◽  
Early Stage ◽  
Critical Role ◽  
Host Cells ◽  
Terminal Domain ◽  
Activation Response ◽  
Tar Rna ◽  
Hiv 1

Recent evidence indicated that HIV-1 Integrase (IN) binds genomic viral RNA (gRNA) playing a critical role in viral particle morphogenesis and gRNA stability in host cells. Combining biophysical and biochemical approaches we show that the C-terminal flexible 18-residues tail of IN acts as a sensor of the peculiar apical structure of trans-activation response element RNA (TAR), directly interacting with its hexaloop. We highlighted how the whole IN C-terminal domain, once bound to TAR, can change its structure assisting the binding of Tat, the HIV trans-activator protein, which finally displaces IN from TAR. Our results are consistent with the emerging role of IN in early stage of proviral transcription and suggest new steps of HIV-1 life cycle that can be considered as therapeutic targets.

scholarly journals Catalytic effectiveness of human aldose reductase. Critical role of C-terminal domain.

1992 ◽  
Vol 267 (29) ◽  
pp. 20965-20970
Author(s):  
K.M. Bohren ◽  
C.E. Grimshaw ◽  
K.H. Gabbay
Keyword(s):  
Aldose Reductase ◽  
Critical Role ◽  
Terminal Domain

scholarly journals The Effect of Octapeptide Repeats on Prion Folding and Misfolding

2021 ◽  
Vol 22 (4) ◽  
pp. 1800
Author(s):  
Kun-Hua Yu ◽  
Mei-Yu Huang ◽  
Yi-Ru Lee ◽  
Yu-Kie Lin ◽  
Hau-Ren Chen ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Age Of Onset ◽  
Prion Diseases ◽  
Critical Role ◽  
Threshold Effect ◽  
Central Feature ◽  
Terminal Domain ◽  
Amyloid Aggregates

Misfolding of prion protein (PrP) into amyloid aggregates is the central feature of prion diseases. PrP has an amyloidogenic C-terminal domain with three α-helices and a flexible tail in the N-terminal domain in which multiple octapeptide repeats are present in most mammals. The role of the octapeptides in prion diseases has previously been underestimated because the octapeptides are not located in the amyloidogenic domain. Correlation between the number of octapeptide repeats and age of onset suggests the critical role of octapeptide repeats in prion diseases. In this study, we have investigated four PrP variants without any octapeptides and with 1, 5 and 8 octapeptide repeats. From the comparison of the protein structure and the thermal stability of these proteins, as well as the characterization of amyloids converted from these PrP variants, we found that octapeptide repeats affect both folding and misfolding of PrP creating amyloid fibrils with distinct structures. Deletion of octapeptides forms fewer twisted fibrils and weakens the cytotoxicity. Insertion of octapeptides enhances the formation of typical silk-like fibrils but it does not increase the cytotoxicity. There might be some threshold effect and increasing the number of peptides beyond a certain limit has no further effect on the cell viability, though the reasons are unclear at this stage. Overall, the results of this study elucidate the molecular mechanism of octapeptides at the onset of prion diseases.

scholarly journals Molecular basis of the dual role of the Mlh1-Mlh3 endonuclease in MMR and in meiotic crossover formation

2021 ◽  
Vol 118 (23) ◽  
pp. e2022704118
Author(s):  
Jingqi Dai ◽  
Aurore Sanchez ◽  
Céline Adam ◽  
Lepakshi Ranjha ◽  
Giordano Reginato ◽  
...  
Keyword(s):  
Meiotic Recombination ◽  
Molecular Basis ◽  
Crystal Packing ◽  
Critical Role ◽  
Holliday Junctions ◽  
Dual Roles ◽  
Terminal Domain ◽  
C Terminus ◽  
Meiotic Crossover

In budding yeast, the MutL homolog heterodimer Mlh1-Mlh3 (MutLγ) plays a central role in the formation of meiotic crossovers. It is also involved in the repair of a subset of mismatches besides the main mismatch repair (MMR) endonuclease Mlh1-Pms1 (MutLα). The heterodimer interface and endonuclease sites of MutLγ and MutLα are located in their C-terminal domain (CTD). The molecular basis of MutLγ’s dual roles in MMR and meiosis is not known. To better understand the specificity of MutLγ, we characterized the crystal structure of Saccharomyces cerevisiae MutLγ(CTD). Although MutLγ(CTD) presents overall similarities with MutLα(CTD), it harbors some rearrangement of the surface surrounding the active site, which indicates altered substrate preference. The last amino acids of Mlh1 participate in the Mlh3 endonuclease site as previously reported for Pms1. We characterized mlh1 alleles and showed a critical role of this Mlh1 extreme C terminus both in MMR and in meiotic recombination. We showed that the MutLγ(CTD) preferentially binds Holliday junctions, contrary to MutLα(CTD). We characterized Mlh3 positions on the N-terminal domain (NTD) and CTD that could contribute to the positioning of the NTD close to the CTD in the context of the full-length MutLγ. Finally, crystal packing revealed an assembly of MutLγ(CTD) molecules in filament structures. Mutation at the corresponding interfaces reduced crossover formation, suggesting that these superstructures may contribute to the oligomer formation proposed for MutLγ. This study defines clear divergent features between the MutL homologs and identifies, at the molecular level, their specialization toward MMR or meiotic recombination functions.

scholarly journals Functional role of C-terminal domain of Thermus thermophilus leucyl-tRNA synthetase

2010 ◽  
Vol 26 (6) ◽  
pp. 478-485 ◽  
Author(s):  
O. I. Gudzera ◽  
A. D. Yaremchuk ◽  
M. A. Tukalo
Keyword(s):  
Functional Role ◽  
Thermus Thermophilus ◽  
Trna Synthetase ◽  
Terminal Domain

scholarly journals Going beyond Integration: The Emerging Role of HIV-1 Integrase in Virion Morphogenesis

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 1005 ◽  
Author(s):  
Jennifer L. Elliott ◽  
Sebla B. Kutluay
Keyword(s):  
Life Cycle ◽  
Viral Genome ◽  
Critical Role ◽  
Viral Rna ◽  
Target Cells ◽  
Host Chromosome ◽  
Virion Morphogenesis ◽  
Rna Genome ◽  
Hiv 1

The HIV-1 integrase enzyme (IN) plays a critical role in the viral life cycle by integrating the reverse-transcribed viral DNA into the host chromosome. This function of IN has been well studied, and the knowledge gained has informed the design of small molecule inhibitors that now form key components of antiretroviral therapy regimens. Recent discoveries unveiled that IN has an under-studied yet equally vital second function in human immunodeficiency virus type 1 (HIV-1) replication. This involves IN binding to the viral RNA genome in virions, which is necessary for proper virion maturation and morphogenesis. Inhibition of IN binding to the viral RNA genome results in mislocalization of the viral genome inside the virus particle, and its premature exposure and degradation in target cells. The roles of IN in integration and virion morphogenesis share a number of common elements, including interaction with viral nucleic acids and assembly of higher-order IN multimers. Herein we describe these two functions of IN within the context of the HIV-1 life cycle, how IN binding to the viral genome is coordinated by the major structural protein, Gag, and discuss the value of targeting the second role of IN in virion morphogenesis.

scholarly journals A VH1-69 antibody lineage from an infected Chinese donor potently neutralizes HIV-1 by targeting the V3 glycan supersite

2020 ◽  
Vol 6 (38) ◽  
pp. eabb1328 ◽  
Author(s):  
Sonu Kumar ◽  
Bin Ju ◽  
Benjamin Shapero ◽  
Xiaohe Lin ◽  
Li Ren ◽  
...  
Keyword(s):  
Cell Sorting ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Viral Escape ◽  
Germline Gene ◽  
Broadly Neutralizing Antibodies ◽  
Functional Studies ◽  
Single Genome ◽  
Hiv 1

An oligomannose patch around the V3 base of HIV-1 envelope glycoprotein (Env) is recognized by multiple classes of broadly neutralizing antibodies (bNAbs). Here, we investigated the bNAb response to the V3 glycan supersite in an HIV-1–infected Chinese donor by Env-specific single B cell sorting, structural and functional studies, and longitudinal analysis of antibody and virus repertoires. Monoclonal antibodies 438-B11 and 438-D5 were isolated that potently neutralize HIV-1 with moderate breadth, are encoded by the VH1-69 germline gene, and have a disulfide-linked long HCDR3 loop. Crystal structures of Env-bound and unbound antibodies revealed heavy chain–mediated recognition of the glycan supersite with a unique angle of approach and a critical role of the intra-HCDR3 disulfide. The mechanism of viral escape was examined via single-genome amplification/sequencing and glycan mutations around the N332 supersite. Our findings further emphasize the V3 glycan supersite as a prominent target for Env-based vaccine design.

scholarly journals The critical role of human transcriptional repressor CTCF mRNA up-regulation in the induction of anti-HIV-1 responses in CD4+ T cells

2008 ◽  
Vol 117 (1) ◽  
pp. 35-44 ◽  
Author(s):  
Yuchang Li ◽  
Guanhua Li ◽  
Anna Ivanova ◽  
Sagiv Aaron ◽  
Malgorzata Simm
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Transcriptional Repressor ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Critical role of PP2A-B56 family protein degradation in HIV-1 Vif mediated G2 cell cycle arrest

2020 ◽  
Vol 527 (1) ◽  
pp. 257-263
Author(s):  
Kayoko Nagata ◽  
Keisuke Shindo ◽  
Yusuke Matsui ◽  
Kotaro Shirakawa ◽  
Akifumi Takaori-Kondo
Keyword(s):  
Cell Cycle ◽  
Protein Degradation ◽  
Cell Cycle Arrest ◽  
Critical Role ◽  
Cycle Arrest ◽  
Family Protein ◽  
G2 Cell Cycle Arrest ◽  
Hiv 1

scholarly journals The mechanism by which molecules containing the HIV gp41 core-binding motif HXXNPF inhibit HIV-1 envelope glycoprotein-mediated syncytium formation

2007 ◽  
Vol 403 (3) ◽  
pp. 565-571 ◽  
Author(s):  
Jing-He Huang ◽  
Heng-Wen Yang ◽  
Shuwen Liu ◽  
Jing Li ◽  
Shibo Jiang ◽  
...  
Keyword(s):  
Envelope Glycoprotein ◽  
Critical Role ◽  
Syncytium Formation ◽  
Phage Clone ◽  
Fusion Process ◽  
Binding Motif ◽  
Active Core ◽  
Different Temperatures ◽  
Hiv 1

The HIV-1 gp41 (glycoprotein 41) core plays a critical role in fusion between the viral and target cell membranes. We previously identified a gp41 core-binding motif, HXXNPF, by screening the phage display peptide libraries. In the present study, we elucidated the mechanism of action of HXXNPF motif-containing molecules of different sizes, including the phage clone L7.8 (a selected positive phage clone), L7.8-g3p* (a 10–kDa fragment of the gene 3 protein) and JCH-4 (a peptide containing 13 residues of L7.8-g3p*), regarding their respective binding abilities to the six-helix bundle and inhibition on syncytium formation at different temperatures. We found that all of the HXXNPF motif-containing molecules could bind to the gp41 core, and that their binding sites may be located in the N-helix domain. L7.8-g3p* and JCH-4 effectively inhibited HIV-1 Env (envelope glycoprotein)-mediated syncytium formation at 37 °C, while the phage clone L7.8 showed no inhibition under the same conditions. However, at suboptimal temperature (31.5 °C), all of these HXXNPF motif-containing molecules were capable of inhibiting syncytium formation. These results suggest that these HXXNPF motif-containing molecules mainly bind to the gp41 core and stop the fusion process mediated by the fusion-active core, resulting in inhibition of HIV-1 fusion and entry. The HXXNPF motif-containing molecules may be used as probes for studying the role of the HIV-1 gp41 core in the late stage of the membrane-fusion process.

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