Signal peptides are allosteric activators of the protein translocase

Giorgos Gouridis, Spyridoula Karamanou, Ioannis Gelis, Charalampos G. Kalodimos, Anastassios Economou

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

Extra-cytoplasmic polypeptides are usually synthesized as preproteins carrying amino-terminal, cleavable signal peptides and secreted across membranes by translocases. The main bacterial translocase comprises the SecYEG protein-conducting channel and the peripheral ATPase motor SecA. Most proteins destined for the periplasm and beyond are exported post-translationally by SecA. Preprotein targeting to SecA is thought to involve signal peptides and chaperones like SecB. Here we show that signal peptides have a new role beyond targeting: they are essential allosteric activators of the translocase. On docking on their binding groove on SecA, signal peptides act in trans to drive three successive states: first, triggering that drives the translocase to a lower activation energy state; second, trapping that engages non-native preprotein mature domains docked with high affinity on the secretion apparatus; and third, secretion during which trapped mature domains undergo several turnovers of translocation in segments. A significant contribution by mature domains renders signal peptides less critical in bacterial secretory protein targeting than currently assumed. Rather, it is their function as allosteric activators of the translocase that renders signal peptides essential for protein secretion. A role for signal peptides and targeting sequences as allosteric activators may be universal in protein translocases.

Original languageEnglish (US)
Pages (from-to)363-367
Number of pages5
JournalNature
Volume462
Issue number7271
DOIs
StatePublished - Nov 19 2009

Bibliographical note

Funding Information:
Acknowledgements We are grateful to G. Dimitrakopoulos for help with MATLAB; M. Koukaki for constructs and materials; D. Boyd, S. Schulman and V. Koronakis for gifts of strains, plasmids and protocols; A. Kohen for advice on Arrhenius plots; A. Kuhn and K. Tokatlidis for comments. The research leading to these results has received funding from the European Community’s Sixth Framework Programme (FP6/2002–2007) under grant agreement LSHC-CT-2006-037834/Streptomics (to A.E.), the Greek General Secretariat of Research and the European Regional Development Fund (PENED03ED623; to A.E.), the US National Institutes of Health grant GM73854 (to C.G.K.) and a Scientist Development Grant by the American Heart Association (to C.G.K.). G.G. is an Onassis Foundation predoctoral fellow.

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