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PEDS Advance Access originally published online on June 2, 2005
Protein Engineering Design and Selection 2005 18(6):285-294; doi:10.1093/protein/gzi030
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Ribosome display of mammalian receptor domains

Bernhard Schimmele, Nico Gräfe and Andreas Plückthun1

Biochemisches Institut der Universität Zürich, Winterthurer Strasse 190, CH-8057 Zürich, Switzerland

1 To whom correspondence should be addressed. E-mail: plueckthun{at}bioc.unizh.ch

Many mammalian receptor domains, among them a large number of potential therapeutic target proteins, are highly aggregation-prone upon heterologous expression in bacteria. This severely limits functional studies of such receptor domains and also their engineering towards improved properties. One of these proteins is the Nogoreceptor, which plays a central role in mediating the inhibition of axon growth and functional recovery after injury of the adult mammalian central nervous system. We show here that the ligand binding domain of the Nogoreceptor folds to an active conformation in ternary ribosomal complexes, as formed in ribosome display. In these complexes the receptor is still connected, via a C-terminal tether, to the peptidyl tRNA in the ribosome and the mRNA also stays connected. The ribosome prevents aggregation of the protein, which aggregates as soon as the release from the ribosome is triggered. In contrast, no active receptor was observed in phage display, where aggregation appears to prevent incorporation of the protein into the phage coat. This strategy sets the stage for rapidly studying defined mutations of such aggregation-prone receptors in vitro and to improve their properties by in vitro evolution using the ribosome display technology.

Keywords: in vitro evolution/nogo receptor/protein aggregation/protein folding/ribosome display

Received April 12, 2005; accepted April 24, 2005.


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