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Large Ankyrin repeat proteins are formed with similar and energetically favorable units.

ABSTRACT: Ankyrin containing proteins are one of the most abundant repeat protein families present in all extant organisms. They are made with tandem copies of similar amino acid stretches that fold into elongated architectures. Here, we built and curated a dataset of 200 thousand proteins that contain 1.2 million Ankyrin regions and characterize the abundance, structure and energetics of the repetitive regions in natural proteins. We found that there is a continuous roughly exponential variety of array lengths with an exceptional frequency at 24 repeats. We described that individual repeats are seldom interrupted with long insertions and accept few deletions, in line with the known tertiary structures. We found that longer arrays are made up of repeats that are more similar to each other than shorter arrays, and display more favourable folding energy, hinting at their evolutionary origin. The array distributions show that there is a physical upper limit to the size of an array of repeats of about 120 copies, consistent with the limit found in nature. The identity patterns within the arrays suggest that they may have originated by sequential copies of more than one Ankyrin unit.

SUBMITTER: Galpern EA

PROVIDER: S-EPMC7314423 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Large Ankyrin repeat proteins are formed with similar and energetically favorable units.

Galpern Ezequiel A EA Freiberger María I MI Ferreiro Diego U DU

PloS one 20200624 6

Ankyrin containing proteins are one of the most abundant repeat protein families present in all extant organisms. They are made with tandem copies of similar amino acid stretches that fold into elongated architectures. Here, we built and curated a dataset of 200 thousand proteins that contain 1.2 million Ankyrin regions and characterize the abundance, structure and energetics of the repetitive regions in natural proteins. We found that there is a continuous roughly exponential variety of array l ...[more]

PMID: 32579546

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Project description:Hypoxia-inducible factor (HIF) is a transcriptional activator with a central role in regulating cellular responses to hypoxia. It is also emerging as a major target for viral manipulation of the cellular environment. Under normoxic conditions, HIF is tightly suppressed by the activity of oxygen-dependent prolyl and asparaginyl hydroxylases. The asparaginyl hydroxylase active against HIF, factor inhibiting HIF (FIH), has also been shown to hydroxylate some ankyrin repeat (ANK) proteins. Using bioinformatic analysis, we identified the five ANK proteins of the parapoxvirus orf virus (ORFV) as potential substrates of FIH. Consistent with this prediction, coimmunoprecipitation of FIH was detected with each of the ORFV ANK proteins, and for one representative ORFV ANK protein, the interaction was shown to be dependent on the ANK domain. Immunofluorescence studies revealed colocalization of FIH and the viral ANK proteins. In addition, mass spectrometry confirmed that three of the five ORFV ANK proteins are efficiently hydroxylated by FIH in vitro While FIH levels were unaffected by ORFV infection, transient expression of each of the ORFV ANK proteins resulted in derepression of HIF-1? activity in reporter gene assays. Furthermore, ORFV-infected cells showed upregulated HIF target gene expression. Our data suggest that sequestration of FIH by ORFV ANK proteins leads to derepression of HIF activity. These findings reveal a previously unknown mechanism of viral activation of HIF that may extend to other members of the poxvirus family. IMPORTANCE:The protein-protein binding motif formed from multiple repeats of the ankyrin motif is common among chordopoxviruses. However, information on the roles of these poxviral ankyrin repeat (ANK) proteins remains limited. Our data indicate that the parapoxvirus orf virus (ORFV) is able to upregulate hypoxia-inducible factor (HIF) target gene expression. This response is mediated by the viral ANK proteins, which sequester the HIF regulator FIH (factor inhibiting HIF). This is the first demonstration of any viral protein interacting directly with FIH. Our data reveal a new mechanism by which viruses reprogram HIF, a master regulator of cellular metabolism, and also show a new role for the ANK family of poxvirus proteins.

Dataset Information

Large Ankyrin repeat proteins are formed with similar and energetically favorable units.

Publications

Large Ankyrin repeat proteins are formed with similar and energetically favorable units.

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