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A natural missing link between activated and downhill protein folding scenarios.

ABSTRACT: We propose protein PTB1 : 4W as a good candidate for engineering into a downhill folder. PTB1 : 4W has a probe-dependent thermal unfolding curve and sub-millisecond T-jump relaxation kinetics on more than one time scale. Its refolding rate in denaturant is a non-linear function of denaturant concentration (curved chevron plot). Yet at high denaturant concentration its unfolding is probe-independent, and the folding kinetics can be fitted to a single exponential decay. The domain appears to fold via a mechanism between downhill folding and activated folding over several small barriers, and when denaturant is added, one of these barriers greatly increases and simplifies the observed folding to apparent two-state kinetics. We predict the simplest free energy function consistent with the thermal denaturation and kinetics experiments by using the singular value Smoluchowski dynamics (SVSD) model. PTB1 : 4W is a natural 'missing link' between downhill and activated folding. We suggest mutations that could move the protein into the downhill folding limit.

SUBMITTER: Liu F

PROVIDER: S-EPMC7382783 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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A natural missing link between activated and downhill protein folding scenarios.

Liu Feng F Maynard Caroline C Scott Gregory G Melnykov Artem A Hall Kathleen B KB Gruebele Martin M

Physical chemistry chemical physics : PCCP 20100211 14

We propose protein PTB1 : 4W as a good candidate for engineering into a downhill folder. PTB1 : 4W has a probe-dependent thermal unfolding curve and sub-millisecond T-jump relaxation kinetics on more than one time scale. Its refolding rate in denaturant is a non-linear function of denaturant concentration (curved chevron plot). Yet at high denaturant concentration its unfolding is probe-independent, and the folding kinetics can be fitted to a single exponential decay. The domain appears to fold ...[more]

PMID: 20336253

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Project description:The origin and deep evolution of retroviruses remain largely unclear. It has been proposed that retroviruses might have originated from a Ty3/Gypsy retrotransposon, but all known Ty3/Gypsy retrotransposons are only distantly related to retroviruses. Retroviruses and some plant Athila/Tat elements (within Ty3/Gypsy retrotransposons) independently evolved a dual RNase H domain and an env/env-like gene. Here, we reported the discovery of a novel lineage of retrotransposons, designated Odin retrotransposons, in the genomes of eight sea anemones (order Actinaria) within the Cnidaria phylum. Odin retrotransposons exhibited unique genome features, encoding a dual RNase H domain (like retroviruses) but no env gene (like most Ty3/Gypsy retrotransposons). Phylogenetic analyses based on reverse transcriptase showed that Odin retrotransposons formed a sister group to lokiretroviruses, and lokiretroviruses and Odin retrotransposons together were sister to canonical retroviruses. Moreover, phylogenetic analyses based on RNase H and integrase also supported the hypothesis that Odin retrotransposons were sisters to lokiretroviruses. Lokiretroviruses and canonical retroviruses did not form a monophyletic group, indicating that lokiretroviruses and canonical retroviruses might represent two distinct virus families. Taken together, the discovery of Odin retrotransposons narrowed down the evolutionary gaps between retrotransposons and canonical retroviruses and lokiretroviruses. IMPORTANCE The origin of retroviruses remains largely unclear. In this study, we discovered a novel retrotransposon lineage, Odin retrotransposons, within the genomes of sea anemones (order Actinaria). In contrast to retroviruses and most retrotransposons, Odin retrotransposons encode a dual RNase H domain but no env gene. Phylogenetic analyses showed that Odin retrotransposons were sisters to lokiretroviruses, and lokiretroviruses and Odin retrotransposons were sisters to retroviruses, establishing an evolutionary framework to decipher the origin of retroviruses (canonical retroviruses and lokiretroviruses). Our results provided insights into the diversity and deep evolution of LTR retrotransposons closely related to retroviruses.

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A natural missing link between activated and downhill protein folding scenarios.

Publications

A natural missing link between activated and downhill protein folding scenarios.

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