Activity-based selection of a proteolytic species using ribosome display

Biochem Biophys Res Commun. 2008 May 23;370(1):77-81. doi: 10.1016/j.bbrc.2008.03.013. Epub 2008 Mar 14.

Abstract

We have examined the potential of displaying a protease species in vitro using ribosome display and demonstrate specific capture on the basis of its catalytic activity. Using a model bacterial cysteine protease, sortase A (SrtA), we show that this enzyme can be functionally expressed in vitro. By overlap PCR we constructed ribosome display templates with the SrtA open reading frame fused to a C terminal glycine-serine rich flexible linker and a tether derived from eGFP. Using the broad range cysteine protease irreversible inhibitor E-64 linked to acrylic beads, we show that we can isolate SrtA ribosome display ternary complexes, and recover their encoding mRNA by RT-PCR. This recovery was lost when applied to a SrtA catalytically inactive mutant, or could be alleviated by competition with free inhibitor. This sensitive technique could be further developed to allow the screening of proteases against putative inhibitors and/or the identification of novel proteolytic species.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoacyltransferases / antagonists & inhibitors
  • Aminoacyltransferases / genetics
  • Aminoacyltransferases / isolation & purification
  • Animals
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / genetics
  • Bacterial Proteins / isolation & purification
  • Catalysis
  • Cysteine Endopeptidases / drug effects
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / isolation & purification*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Humans
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Methods
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribosomes / enzymology*

Substances

  • Bacterial Proteins
  • Cysteine Proteinase Inhibitors
  • RNA, Messenger
  • Aminoacyltransferases
  • sortase A
  • Cysteine Endopeptidases
  • Leucine
  • E 64