Nature Structural & Molecular Biology
12, 870 - 878 (2005)
Published online: 25 September 2005; | doi:10.1038/nsmb994
Sequential triage of transmembrane segments by Sec61 during biogenesis of a native multispanning membrane proteinHeather Sadlish1, 4, David Pitonzo1, 4, Arthur E Johnson2, 3
& William R Skach11
Department of Biochemistry and Molecular Biology, Oregon Health & Sciences University, Portland, Oregon 97239, USA. 2
Department of Medical Biochemistry and Genetics, Texas A&M University System, Health Science Center, College Station, Texas 77843-1114, USA. 3
Departments of Chemistry and of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-1114, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to William R Skach skachw@ohsu.edu During polytopic protein biogenesis, the Sec61 translocon must rapidly orient and integrate multiple transmembrane segments (TMs) into the endoplasmic reticulum membrane. To understand this process, we examined interactions between Sec61 and all six TMs of the aquaporin-4 (AQP4) water channel at defined stages of synthesis using incorporated photo-cross-linking probes. Each TM interacted with and moved through the translocon in a highly ordered and sequential fashion. Strong asymmetric Sec61 cross-linking was observed for only one helix at a time, suggesting the presence of a single primary binding site. However, up to four TMs simultaneously contacted Sec61 from different molecular environments. Thus, AQP4 integration by Sec61 involves sequential triage of TMs from their initial portal of entry into multiple secondary sites within the translocon. This mechanism provides a means to facilitate early folding events before release into the lipid bilayer.
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