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Title: Receptor compaction and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER
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 SRP54 G226E 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.  more » « less
Award ID(s):
1929452
NSF-PAR ID:
10354886
Author(s) / Creator(s):
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Date Published:
Journal Name:
Science Advances
Volume:
7
Issue:
21
ISSN:
2375-2548
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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