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Published 31 January 2005. doi:10.1083/jcb.200409174
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 3, 389-399
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Article

 The molecular mechanisms underlying BiP-mediated gating of the Sec61 translocon of the endoplasmic reticulum

Nathan N. Alder1, Ying Shen2,3, Jeffrey L. Brodsky4, Linda M. Hendershot2,3, and Arthur E. Johnson1,5,6

1 Department of Medical Biochemistry and Genetics, Texas A&M University System Health Science Center, College Station, TX 77843
2 Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105
3 Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163
4 Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260
5 Department of Chemistry, Texas A&M University, College Station, TX 77843
6 Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843

Correspondence to Arthur E. Johnson: aejohnson{at}tamu.edu

The Sec61 translocon of the endoplasmic reticulum membrane forms an aqueous pore that is gated by the lumenal Hsp70 chaperone BiP. We have explored the molecular mechanisms governing BiP-mediated gating activity, including the coupling between gating and the BiP ATPase cycle, and the involvement of the substrate-binding and J domain–binding regions of BiP. Translocon gating was assayed by measuring the collisional quenching of fluorescent probes incorporated into nascent chains of translocation intermediates engaged with microsomes containing various BiP mutants and BiP substrate. Our results indicate that BiP must assume the ADP-bound conformation to seal the translocon, and that the reopening of the pore requires an ATP binding–induced conformational change. Further, pore closure requires functional interactions between both the substrate-binding region and the J domain–binding region of BiP and membrane proteins. The mechanism by which BiP mediates translocon pore closure and opening is therefore similar to that in which Hsp70 chaperones associate with and dissociate from substrates.

Abbreviations used in this paper: I–, iodide ion; KRM, salt-washed ER microsome; pPL, preprolactin; rBiP, recombinant hamster BiP; RNC, ribosome-nascent chain complex; RRM, reconstituted microsome; SBD, substrate-binding domain; SRP, signal recognition particle; XRM, lumen-extracted microsome.


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