Abstract
Targeting of most integral membrane proteins to the endoplasmic reticulum is controlled by the signal recognition particle, which recognizes a hydrophobic signal sequence near the protein N terminus. Proper folding of these proteins is monitored by the unfolded protein response and involves protein degradation pathways to ensure quality control. Here, we identify a new pathway for quality control of major facilitator superfamily transporters that occurs before the first transmembrane helix, the signal sequence recognized by the signal recognition particle, is made by the ribosome. Increased rates of translation elongation of the N-terminal sequence of these integral membrane proteins can divert the nascent protein chains to the ribosome-associated complex and stress-seventy subfamily B chaperones. We also show that quality control of integral membrane proteins by ribosome-associated complex-stress-seventy subfamily B couples translation rate to the unfolded protein response, which has implications for understanding mechanisms underlying human disease and protein production in biotechnology.
Highlights
Targeting of most integral membrane proteins to the endoplasmic reticulum is controlled by the signal recognition particle, which recognizes a hydrophobic signal sequence near the protein N terminus
ER-associated degradation pathway (ERAD) serves as a quality control mechanism for membrane proteins post-translationally, less is known about quality control of membrane proteins before they are targeted to the translocon in the endoplasmic reticulum (ER) [25]
Our results suggest that RACSsb acts in the quality control of integral membrane proteins by actively sensing translation elongation rates of nascent membrane proteins on the ribosome
Summary
Targeting of most integral membrane proteins to the endoplasmic reticulum is controlled by the signal recognition particle, which recognizes a hydrophobic signal sequence near the protein N terminus. SRPtarget binding is mediated by the nascent polypeptide– associated complex (NAC), which prevents nonspecific binding of SRP to non-secretory substrates and deters antagonistic interactions between SRP and N terminus–modifying enzymes during scanning of nascent polypeptides (9 –11) These early targeting steps are crucial for proper membrane protein insertion into the ER and to prevent proteostatic stress due to the aggregation of the highly hydrophobic transmembrane helices of membrane proteins in the cytosol [5]. RAC-Ssb and integral membrane protein translation encoded slowdown of translation (REST) elements of non-optimal codons 30 – 40 codons downstream of the signal sequence/TM1 that assisted SRP interactions through slowing translation elongation All of these studies relied on computational methods to discern patterns of codon usage bias. We present experimental evidence for a new quality control mechanism that couples translation rates of the N terminus of MFS transporters to the chaperone machinery at the ribosome exit tunnel, which may contribute to proper SRP interactions with these ribosome–nascent chains
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
