Dataset Information

HIV-1 Reverse Transcriptase: A Metamorphic Protein with Three Stable States.

ABSTRACT: There has been a steadily increasing appreciation of the fact that the relationship between protein sequence and structure is often sufficiently ambiguous to allow a single sequence to adopt alternative, stable folds. Living organisms have been able to utilize such metamorphic proteins in remarkable and unanticipated ways. HIV-1 reverse transcriptase is among the earliest such proteins identified and remains a unique example in which a functional heterodimer contains two, alternatively folded polymerase domains. Structural characterization of the p66 precursor protein combined with NMR spectroscopic and molecular modeling studies have provided insights into the factors underlying the metamorphic transition and the subunit-specific programmed unfolding step required to expose the protease cleavage site within the ribonuclease H domain, supporting the conversion of the p66/p66' precursor into the mature p66/p51 heterodimer.

SUBMITTER: London RE

PROVIDER: S-EPMC6686890 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

HIV-1 Reverse Transcriptase: A Metamorphic Protein with Three Stable States.

London Robert E RE

Structure (London, England : 1993) 20190110 3

There has been a steadily increasing appreciation of the fact that the relationship between protein sequence and structure is often sufficiently ambiguous to allow a single sequence to adopt alternative, stable folds. Living organisms have been able to utilize such metamorphic proteins in remarkable and unanticipated ways. HIV-1 reverse transcriptase is among the earliest such proteins identified and remains a unique example in which a functional heterodimer contains two, alternatively folded po ...[more]

PMID: 30639227

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Project description:The replication of human immunodeficiency virus-1 (HIV-1) requires reverse transcription of the viral RNA genome and integration of newly synthesized pro-viral DNA into the host genome. This is mediated by the viral proteins reverse transcriptase (RT) and integrase (IN). The formation and stabilization of the pre-integration complex (PIC), which is an essential step for reverse transcription, nuclear import, chromatin targeting, and subsequent integration, involves direct and indirect modes of interaction between RT and IN proteins. While epitope-based treatments targeting IN-viral DNA and IN-RT complexes appear to be a promising combination for an anti-HIV treatment, the mechanisms of IN-RT interactions within the PIC are not well understood due to the transient nature of the protein complex and the intrinsic flexibility of its components. Here, we identify potentially interacting regions between the IN and RT proteins within the PIC through the coevolutionary analysis of amino acid sequences of the two proteins. Our results show that specific regions in the two proteins have strong coevolutionary signatures, suggesting that these regions either experience direct and prolonged interactions between them that require high affinity and/or specificity or that the regions are involved in interactions mediated by dynamic conformational changes and, hence, may involve both direct and indirect interactions. Other regions were found to exhibit weak, but positive correlations, implying interactions that are likely transient and/or have low affinity. We identified a series of specific regions of potential interactions between the IN and RT proteins (e.g., specific peptide regions within the C-terminal domain of IN were identified as potentially interacting with the Connection domain of RT). Coevolutionary analysis can serve as an important step in predicting potential interactions, thus informing experimental studies. These studies can be integrated with structural data to gain a better understanding of the mechanisms of HIV protein interactions.

Dataset Information

HIV-1 Reverse Transcriptase: A Metamorphic Protein with Three Stable States.

Publications

HIV-1 Reverse Transcriptase: A Metamorphic Protein with Three Stable States.

Similar Datasets

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