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J. Biol. Chem., Vol. 281, Issue 10, 6539-6545, March 10, 2006

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Trigger Factor Forms a Protective Shield for Nascent Polypeptides at the Ribosome^*

From the Zentrum für Molekulare Biologie Heidelberg (ZMBH), Im Neuenheimer Feld 282, Universität Heidelberg, 69120 Heidelberg, Germany

In prokaryotes, the ribosome-associated Trigger Factor is the first chaperone newly synthesized polypeptides encounter when they emerge from the ribosomal exit tunnel. The effects that Trigger Factor exerts on nascent polypeptides, however, remain unclear. Here we analyzed the potential of the Trigger Factor to shield nascent polypeptides at the ribosome. A set of arrested nascent polypeptides differing in origin, size, and folding status were synthesized in an Escherichia coli-based in vitro transcription/translation system and tested for sensitivity to degradation by the unspecific protease proteinase K. In the absence of Trigger Factor, nascent polypeptides exposed outside the ribosomal exit tunnel were rapidly degraded unless they were folded into a compact domain. The presence of Trigger Factor, as well as a Trigger Factor fragment lacking its peptidyl-prolyl isomerase domain, counteracted degradation of all unfolded nascent polypeptides tested. This protective function was specific for ribosome-tethered Trigger Factor, since neither non-ribosomal Trigger Factor nor the DnaK system, which cooperates with Trigger Factor in the folding process in vivo, revealed a comparable efficiency in protection. Furthermore, shielding by Trigger Factor was not restricted to short stretches of nascent chains but was evident for large, non-native nascent polypeptides exposing up to 41 kDa outside the ribosome. We suggest that Trigger Factor supports productive de novo folding by shielding nascent polypeptides on the ribosome thereby preventing untimely degradation or aggregation processes. This protected environment provided by Trigger Factor might be particularly important for large multidomain proteins to fold productively into their native states.

Received for publication, November 17, 2005 , and in revised form, January 4, 2006.

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (to B. B. and E. D.) and the Human Frontier Science Program (to E. D), a Heisenberg Fellowship from the DFG (to E. D.), a fellowship from the Boehringer Ingelheim Fonds (to A. H.), and by a grant from the Fonds der Chemischen Industrie (to B. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹To whom correspondence may be addressed. Tel.: 49-6221-546870; Fax: 49-6221-545894; E-mail: e.deuerling{at}zmbh.uni-heidelberg.de. ²To whom correspondence may be addressed. Tel.: 49-6221-546870; Fax: 49-6221-545894; E-mail: bukau{at}zmbh.uni-heidelberg.de.

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