TY - JOUR
T1 - Quality control of integral membrane proteins by assembly-dependent membrane integration
AU - Feige, Matthias J.
AU - Hendershot, Linda M.
N1 - Funding Information:
We are grateful to Julia Behnke and Drs. Johannes Buchner, Joseph Opferman, Joel Otero, Janet Partridge, and Brenda Schulman for helpful comments on the manuscript. We thank Art Weiss, UCSF, for kindly sharing J.RT-T3.1 cells and Yuval Reiss, Proteologics/Israel, for sharing the Hrd1 C291S plasmid. M.J.F. acknowledges funding by the German Academy of Sciences Leopoldina, grant number LPDS 2009-32, and by the Paul Barrett-endowed fellowship of St. Jude. We are grateful to the Hartwell center of St. Jude for DNA sequencing. This work was funded by NIH grants R03 AI097733 and R01 GM54068 and by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. M.J.F. and L.M.H. designed the study. M.J.F. performed experiments. M.J.F. and L.M.H. analyzed data and wrote the manuscript.
PY - 2013/8/8
Y1 - 2013/8/8
N2 - Cell-surface multiprotein complexes are synthesized in the endoplasmic reticulum (ER), where they undergo cotranslational membrane integration and assembly. The quality control mechanisms that oversee these processes remain poorly understood. We show that less hydrophobic transmembrane (TM) regions derived from several single-pass TM proteins can enter the ER lumen completely. Once mislocalized, they are recognized by the Hsp70 chaperone BiP. In a detailed analysis for one of these proteins, the αβT cell receptor (αβTCR), we show that unassembled ER-lumenal subunits are rapidly degraded, whereas specific subunit interactions en route to the native receptor promote membrane integration of the less hydrophobic TM segments, thereby stabilizing the protein. For the TCR α chain, both complete ER import and subunit assembly depend on the same pivotal residue in its TM region. Thus, membrane integration linked to protein assembly allows cellular quality control of membrane proteins and connects the lumenal ER chaperone machinery to membrane protein biogenesis.
AB - Cell-surface multiprotein complexes are synthesized in the endoplasmic reticulum (ER), where they undergo cotranslational membrane integration and assembly. The quality control mechanisms that oversee these processes remain poorly understood. We show that less hydrophobic transmembrane (TM) regions derived from several single-pass TM proteins can enter the ER lumen completely. Once mislocalized, they are recognized by the Hsp70 chaperone BiP. In a detailed analysis for one of these proteins, the αβT cell receptor (αβTCR), we show that unassembled ER-lumenal subunits are rapidly degraded, whereas specific subunit interactions en route to the native receptor promote membrane integration of the less hydrophobic TM segments, thereby stabilizing the protein. For the TCR α chain, both complete ER import and subunit assembly depend on the same pivotal residue in its TM region. Thus, membrane integration linked to protein assembly allows cellular quality control of membrane proteins and connects the lumenal ER chaperone machinery to membrane protein biogenesis.
UR - http://www.scopus.com/inward/record.url?scp=84881536447&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2013.07.013
DO - 10.1016/j.molcel.2013.07.013
M3 - Article
C2 - 23932713
AN - SCOPUS:84881536447
SN - 1097-2765
VL - 51
SP - 297
EP - 309
JO - Molecular Cell
JF - Molecular Cell
IS - 3
ER -