HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 41, 27504-27513, October 10, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/41/27504    most recent M804591200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rabu, C. Articles by High, S. Search for Related Content PubMed PubMed Citation Articles by Rabu, C. Articles by High, S. Social Bookmarking                      What's this?

A Precursor-specific Role for Hsp40/Hsc70 during Tail-anchored Protein Integration at the Endoplasmic Reticulum^*

Catherine Rabu, Peter Wipf, Jeffrey L. Brodsky^¶, and Stephen High¹

From the Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom, the Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, and the ^¶Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

Tail-anchored (TA) protein synthesis at the endoplasmic reticulum (ER) represents a distinct and novel process that provides a paradigm for understanding post-translational membrane insertion in eukaryotes. The major route for delivering TA proteins to the ER requires both ATP and one or more cytosolic factors that facilitate efficient membrane insertion. Until recently, the identity of these cytosolic components was elusive, but two candidates have now been suggested to promote ATP-dependent TA protein integration. The first is the cytosolic chaperone complex of Hsp40/Hsc70, and the second is a novel ATPase denoted Asna-1 or TRC40. In this study we focus on the role of the Hsp40/Hsc70 complex in promoting TA protein biogenesis at the ER. We show that the membrane integration of most TA proteins is stimulated by Hsp40/Hsc70 when using purified components and a reconstituted system. In contrast, when both Hsp40/Hsc70 and Asna-1/TRC40 are provided as a complete system, small molecule inhibition of Hsp40/Hsc70 indicates that only a subset of TA proteins are obligatory clients for this chaperone-mediated delivery route. We show that the hydrophobicity of the TA region dictates whether a precursor is delivered to the ER via the Hsp40/Hsc70 or Asna-1/TRC40-dependent route, and we conclude that these distinct cytosolic ATPases are responsible for two different ATP-dependent pathways of TA protein biogenesis.

Received for publication, June 16, 2008

Note Added in Proof—M. Schuldiner et al. (2008) Cell 134, 634–645, have recently shown that the yeast Asna-1 homologue, Get 3, promotes TA protein membrane insertion at the ER via interaction with the Get1/Get2 membrane receptor complex.

^* This work was supported, in whole or in part, by National Institutes of Health Grant P50-GM067082 from the NIGMS for support of the P50 Chemical Methodologies and Library Development Program at the University of Pittsburgh (to P. W.). This work was also supported by a Biotechnology and Biological Sciences Research Council project grant (to S. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1, S2, and S3.

¹ To whom correspondence should be addressed. Tel.: 44-161-275-5070; E-mail: stephen.high{at}manchester.ac.uk.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. F. Colombo, R. Longhi, and N. Borgese The role of cytosolic proteins in the insertion of tail-anchored proteins into phospholipid bilayers J. Cell Sci., July 15, 2009; 122(14): 2383 - 2392. [Abstract] [Full Text] [PDF]