2. Academic Validation
  3. Receptor compaction and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER

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

  • Sci Adv. 2021 May 21;7(21):eabg0942. doi: 10.1126/sciadv.abg0942.
Jae Ho Lee 1,  Ahmad Jomaa 2,  SangYoon Chung 3,  Yu-Hsien Hwang Fu 1,  Ruilin Qian 1,  Xuemeng Sun 1,  Hao-Hsuan Hsieh 1,  Sowmya Chandrasekar 1,  Xiaotian Bi 1,  Simone Mattei 4,  Daniel Boehringer 4 5,  Shimon Weiss 3 6,  Nenad Ban 2,  Shu-Ou Shan 7
Affiliations

Affiliations

  • 1 Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
  • 2 Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland. [email protected] [email protected] [email protected].
  • 3 Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 4 Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland.
  • 5 Cryo-EM Knowledge Hub, ETH Zurich, 8093 Zurich, Switzerland.
  • 6 Department of Physics, Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, 52900 Ramat-Gan, Israel.
  • 7 Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA. [email protected] [email protected] [email protected].
PMID: 34020957 DOI: 10.1126/sciadv.abg0942
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.

Figures