Sequential activation of human signal recognition particle by the ribosome and signal sequence drives efficient protein targeting

Proceedings of the National Academy of Sciences of the United States of America
Jae Ho LeeShu-Ou Shan

Abstract

Signal recognition particle (SRP) is a universally conserved targeting machine that mediates the targeted delivery of ∼30% of the proteome. The molecular mechanism by which eukaryotic SRP achieves efficient and selective protein targeting remains elusive. Here, we describe quantitative analyses of completely reconstituted human SRP (hSRP) and SRP receptor (SR). Enzymatic and fluorescence analyses showed that the ribosome, together with a functional signal sequence on the nascent polypeptide, are required to activate SRP for rapid recruitment of the SR, thereby delivering translating ribosomes to the endoplasmic reticulum. Single-molecule fluorescence spectroscopy combined with cross-complementation analyses reveal a sequential mechanism of activation whereby the ribosome unlocks the hSRP from an autoinhibited state and primes SRP to sample a variety of conformations. The signal sequence further preorganizes the mammalian SRP into the optimal conformation for efficient recruitment of the SR. Finally, the use of a signal sequence to activate SRP for receptor recruitment is a universally conserved feature to enable efficient and selective protein targeting, and the eukaryote-specific components confer upon the mammalian SRP the ab...Continue Reading

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Citations

Sep 21, 2019·The Journal of Cell Biology·Yu-Hsien Hwang FuShu-Ou Shan
Aug 14, 2019·Biological Chemistry·Klemens WildIrmgard Sinning
Feb 2, 2019·Journal of Bioenergetics and Biomembranes·Jon K Cherry, Cheryl A Woolhead
Oct 13, 2020·Frontiers in Cell and Developmental Biology·Masanori HonshoYukio Fujiki
Feb 6, 2021·Nature Communications·Ying ZhangSabine Rospert

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