Action of the bacterial alarmones (p)ppGpp on translational GTPases
Abstract Ribosomes are intricate and highly complex macromolecular structures. Their maturation into fully functional entities is aided by a vast number of accessory proteins, many of which belong to the class of GTPases. GTPases do furthermore play pivotal roles during protein biosynthesis, during...
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Ribosomes are intricate and highly complex macromolecular structures. Their maturation into fully functional entities is aided by a vast number of accessory proteins, many of which belong to the class of GTPases. GTPases do furthermore play pivotal roles during protein biosynthesis, during which the genetic code in the form of transcribed mRNA is translated into functional proteins.
The nutritional alarmones ppGpp and pppGpp, collectively abbreviated as (p)ppGpp or alarmones, are nucleotide-based second messenger molecules, the synthesis of which is linked to the onset of numerous unfavorable environmental conditions, in particular limitations in the availability of amino acids. Owing to the similarities of the (p)ppGpp compounds with the GTPase-directed GTP and GDP molecules, a direct regulation of ribosomal and translational GTPases is highly conceivable and documented in literature. However, a structural and mechanistic understanding of the action of (p)ppGpp and how precisely they interfere with GTPase functionality, are less well understood. This work aimed to fill this gap of knowledge.
Selected ribosomal and translational GTPases were purified and probed for their ability to interact with (p)ppGpp. The crystal structure of Escherichia coli elongation factor Tu (EF-Tu) could be obtained in presence of ppGpp and provides a rationale for inhibition of translation elongation by (p)ppGpp. Furthermore, alarmone binding to three GTPases involved in maturation of the prokaryotic ribosome was substantiated by various biophysical approaches evidencing that (p)ppGpp should interfere with their cellular function through competition with the natural substrate GTP. Although further implications of (p)ppGpp interference with ribosomal GTPases could not be substantiated in this work, it settles the stage for further in-depth mechanistic and functional studies on these target proteins.|
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