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Dimerization of the lutropin receptor: insights from computational modeling.

ABSTRACT: A computational approach based upon rigid-body docking, ad hoc filtering, and cluster analysis has been carried out to predict likely interfaces in LHR homodimers. Quaternary structure predictions emphasize the role of helices 4, 5 and 6, with prominence to helix 4, in mediating inter-monomer interactions. Intermolecular interactions essentially involve the transmembrane domains rather than the hydrophilic loops and do not implicate disulfide bridges.Collectively, molecular dynamics simulations on the isolated receptor and computational modeling of LHR homodimerization suggest that mutation-induced LHR activation favors H4-H4 contacts involving the highly conserved W491 from both the receptors monomers.

SUBMITTER: Fanelli F

PROVIDER: S-EPMC1994142 | biostudies-literature | 2007 Jan

REPOSITORIES: biostudies-literature

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Dimerization of the lutropin receptor: insights from computational modeling.

Fanelli F F

Molecular and cellular endocrinology 20061018

A computational approach based upon rigid-body docking, ad hoc filtering, and cluster analysis has been carried out to predict likely interfaces in LHR homodimers. Quaternary structure predictions emphasize the role of helices 4, 5 and 6, with prominence to helix 4, in mediating inter-monomer interactions. Intermolecular interactions essentially involve the transmembrane domains rather than the hydrophilic loops and do not implicate disulfide bridges.Collectively, molecular dynamics simulations ...[more]

PMID: 17052834

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Project description:BackgroundThe lentiviral Rev protein mediates nuclear export of intron-containing viral RNAs that encode structural proteins or serve as the viral genome. Following translation, HIV-1 Rev localizes to the nucleus and binds its cognate sequence, termed the Rev-responsive element (RRE), in incompletely spliced viral RNA. Rev subsequently multimerizes along the viral RNA and associates with the cellular Crm1 export machinery to translocate the RNA-protein complex to the cytoplasm. Equine infectious anemia virus (EIAV) Rev is functionally homologous to HIV-1 Rev, but shares very little sequence similarity and differs in domain organization. EIAV Rev also contains a bipartite RNA binding domain comprising two short arginine-rich motifs (designated ARM-1 and ARM-2) spaced 79 residues apart in the amino acid sequence. To gain insight into the topology of the bipartite RNA binding domain, a computational approach was used to model the tertiary structure of EIAV Rev.ResultsThe tertiary structure of EIAV Rev was modeled using several protein structure prediction and model quality assessment servers. Two types of structures were predicted: an elongated structure with an extended central alpha helix, and a globular structure with a central bundle of helices. Assessment of models on the basis of biophysical properties indicated they were of average quality. In almost all models, ARM-1 and ARM-2 were spatially separated by >15 Å, suggesting that they do not form a single RNA binding interface on the monomer. A highly conserved canonical coiled-coil motif was identified in the central region of EIAV Rev, suggesting that an RNA binding interface could be formed through dimerization of Rev and juxtaposition of ARM-1 and ARM-2. In support of this, purified Rev protein migrated as a dimer in Blue native gels, and mutation of a residue predicted to form a key coiled-coil contact disrupted dimerization and abrogated RNA binding. In contrast, mutation of residues outside the predicted coiled-coil interface had no effect on dimerization or RNA binding.ConclusionsOur results suggest that EIAV Rev binding to the RRE requires dimerization via a coiled-coil motif to juxtapose two RNA binding motifs, ARM-1 and ARM-2.

Dataset Information

Dimerization of the lutropin receptor: insights from computational modeling.

Publications

Dimerization of the lutropin receptor: insights from computational modeling.

Similar Datasets

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