Molecular strategy for blocking isopeptide bond formation in nascent pilin proteins

Proceedings of the National Academy of Sciences of the United States of America
Jaime Andrés Rivas-PardoJulio M Fernandez

Abstract

Bacteria anchor to their host cells through their adhesive pili, which must resist the large mechanical stresses induced by the host as it attempts to dislodge the pathogens. The pili of gram-positive bacteria are constructed as a single polypeptide made of hundreds of pilin repeats, which contain intramolecular isopeptide bonds strategically located in the structure to prevent their unfolding under force, protecting the pilus from degradation by extant proteases and oxygen radicals. Here, we demonstrate the design of a short peptide that blocks the formation of the isopeptide bond present in the pilin Spy0128 from the human pathogen Streptococcus pyogenes, resulting in mechanically labile pilin domains. We use a combination of protein engineering and atomic-force microscopy force spectroscopy to demonstrate that the peptide blocks the formation of the native isopeptide bond and compromises the mechanics of the domain. While an intact Spy0128 is inextensible at any force, peptide-modified Spy0128 pilins readily unfold at very low forces, marking the abrogation of the intramolecular isopeptide bond as well as the absence of a stable pilin fold. We propose that isopeptide-blocking peptides could be further developed as a type of ...Continue Reading

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Citations

Jan 10, 2020·Molecular Microbiology·Felipe VielaYves F Dufrêne
Aug 8, 2020·The FEBS Journal·Sabita SharmaIonel Popa
Dec 2, 2020·Nature Chemistry·Alvaro Alonso-CaballeroJulio M Fernandez
Feb 27, 2021·Frontiers in Microbiology·Stefan Ness, Markus Hilleringmann
Apr 4, 2021·Cells·Ashwini ShindeTuhin Subhra Santra
Mar 2, 2021·Annual Review of Biophysics·Souradeep BanerjeeShubhasis Haldar
Jul 24, 2021·Molecular Aspects of Medicine·Vinay SharmaVengadesan Krishnan

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