Receptor compaction and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER

Jae Ho Lee, Ahmad Jomaa, Sang Yoon Chung, Yu Hsien Hwang Fu, Ruilin Qian, Xuemeng Sun, Hao Hsuan Hsieh, Sowmya Chandrasekar, Xiaotian Bi, Simone Mattei, Daniel Boehringer, Shimon Weiss, Nenad Ban, Shu Ou Shan

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12 Scopus citations

Abstract

The conserved signal recognition particle (SRP) cotranslationally delivers ~30% of the proteome to the eukaryotic endoplasmic reticulum (ER). The molecular mechanism by which eukaryotic SRP transitions from cargo recognition in the cytosol to protein translocation at the ER is not understood. Here, structural, biochemical, and single-molecule studies show that this transition requires multiple sequential conformational rearrangements in the targeting complex initiated by guanosine triphosphatase (GTPase)–driven compaction of the SRP receptor (SR). Disruption of these rearrangements, particularly in mutant SRP54G226E linked to severe congenital neutropenia, uncouples the SRP/SR GTPase cycle from protein translocation. Structures of targeting intermediates reveal the molecular basis of early SRP-SR recognition and emphasize the role of eukaryote-specific elements in regulating targeting. Our results provide a molecular model for the structural and functional transitions of SRP throughout the targeting cycle and show that these transitions provide important points for biological regulation that can be perturbed in genetic diseases.

Original languageEnglish
Article numbereabg0942
JournalScience advances
Volume7
Issue number21
DOIs
StatePublished - May 2021

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