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A yeast system for discovering optogenetic inhibitors of eukaryotic translation initiation.

08:00 EDT 22nd March 2019 | BioPortfolio

Summary of "A yeast system for discovering optogenetic inhibitors of eukaryotic translation initiation."

The precise spatiotemporal regulation of protein synthesis is essential for many complex biological processes such as memory formation, embryonic development and tumor formation. Current methods used to study protein synthesis offer only a limited degree of spatiotemporal control. Optogenetic methods, in contrast, offer the prospect of controlling protein synthesis non-invasively within minutes and with a spatial scale as small as a single synapse. Here, we present a hybrid yeast system where growth depends on the activity of human eukaryotic initiation factor 4E (eIF4E) that is suitable for screening optogenetic designs for the down-regulation of protein synthesis. We used this system to screen a diverse initial panel of 15 constructs designed to couple a light switchable domain (PYP, RsLOV, LOV, Dronpa) to 4EBP2 (eukaryotic initiation factor 4E binding protein 2), a native inhibitor of translation initiation. We identified cLIPS1 (circularly permuted LOV inhibitor of protein synthesis 1), a fusion of a segment of 4EBP2 and a circularly permuted version of the LOV2 domain from Avena sativa, as a photo-activated inhibitor of translation. Adapting the screen for higher throughput, we tested small libraries of cLIPS1 variants and found cLIPS2, a construct with an improved degree of optical control. We show that these constructs can both inhibit translation in yeast harboring a human eIF4E in vivo, and bind human eIF4E in vitro in a light-dependent manner. This hybrid yeast system thus provides a convenient way for discovering optogenetic constructs that can regulate of human eIF4E-depednednt translation initiation in a mechanistically defined manner.

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This article was published in the following journal.

Name: ACS synthetic biology
ISSN: 2161-5063
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A component of eukaryotic initiation factor-4F that is involved in multiple protein interactions at the site of translation initiation. Thus it may serve a role in bringing together various initiation factors at the site of translation initiation.

A trimeric peptide initiation factor complex that associates with the 5' MRNA cap structure of RNA (RNA CAPS) and plays an essential role in MRNA TRANSLATION. It is composed of EUKARYOTIC INITIATION FACTOR-4A; EUKARYOTIC INITIATION FACTOR-4E; and EUKARYOTIC INITIATION FACTOR-4G.

Peptide initiation factors from eukaryotic organisms. Over twelve factors are involved in PEPTIDE CHAIN INITIATION, TRANSLATIONAL in eukaryotic cells. Many of these factors play a role in controlling the rate of MRNA TRANSLATION.

A eukaryotic initiation factor that binds to 40S ribosomal subunits. Although initially considered a "non-essential" factor for eukaryotic transcription initiation, eukaryotic initiation factor-1 is now thought to play an important role in localizing RIBOSOMES at the initiation codon of MRNA.

A eukaryotic initiation factor that interacts with the 40S initiation complex and promotes the hydrolysis of the bound GTP. The hydrolysis of GTP causes the release of EUKARYOTIC INITIATION FACTOR-2 and EUKARYOTIC INITIATION FACTOR-3 from the 40S subunit and the subsequent joining of the 60S ribosomal subunit to the 40S complex to form the functional 80S initiation complex

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