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Differential modes of orphan subunit recognition for the WRB/CAML complex

Inglis, Alison J. and Page, Katharine R. and Guna, Alina and Voorhees, Rebecca M. (2020) Differential modes of orphan subunit recognition for the WRB/CAML complex. Cell Reports, 30 (11). pp. 3691-3698. ISSN 2211-1247. PMCID PMC7147533. doi:10.1016/j.celrep.2020.02.084.

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A large proportion of membrane proteins must be assembled into oligomeric complexes for function. How this process occurs is poorly understood, but it is clear that complex assembly must be tightly regulated to avoid accumulation of orphan subunits with potential cytotoxic effects. We interrogated assembly in mammalian cells by using the WRB/CAML complex, an essential insertase for tail-anchored proteins in the endoplasmic reticulum (ER), as a model system. Our data suggest that the stability of each subunit is differentially regulated. In WRB’s absence, CAML folds incorrectly, causing aberrant exposure of a hydrophobic transmembrane domain to the ER lumen. When present, WRB can correct the topology of CAML both in vitro and in cells. In contrast, WRB can independently fold correctly but is still degraded in the absence of CAML. We therefore propose that there are at least two distinct regulatory pathways for the surveillance of orphan subunits in the mammalian ER.

Item Type:Article
Related URLs:
URLURL TypeDescription Paper CentralArticle
Inglis, Alison J.0000-0002-9008-8565
Guna, Alina0000-0003-0757-1255
Voorhees, Rebecca M.0000-0003-1640-2293
Additional Information:© 2020 The Authors. This is an open access article under the CC BY-NC-ND license ( Received 17 September 2019, Revised 23 December 2019, Accepted 24 February 2020, Available online 17 March 2020. We thank T. Pleiner for help with GFP affinity purification and the Caltech Flow Cytometry facility for their help with fluorescence-activated cell sorting (FACS) experiments. Confocal imaging was performed in the Caltech Biological Imaging Facility, with the support of the Caltech Beckman Institute and the Arnold and Mabel Beckman Foundation. The antibody against 3F4 was a kind gift from Ramanujan S. Hegde. This work was supported by the Heritage Medical Research Institute, the Kinship Foundation, the Pew-Stewart Foundation, and the National Institutes of Health National Institute of General Medical Sciences under award number DP2GM137412. Author Contributions: A.J.I., A.G., and R.M.V. conceived and designed the study. A.J.I., K.R.P., and A.G. performed the experiments. R.M.V. wrote the manuscript with input from all authors. The authors declare no conflict of interest.
Group:Heritage Medical Research Institute
Funding AgencyGrant Number
Heritage Medical Research InstituteUNSPECIFIED
Kinship FoundationUNSPECIFIED
Pew-Stewart FoundationUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Arnold and Mabel Beckman FoundationUNSPECIFIED
Subject Keywords:membrane proteins; endoplasmic reticulum; quality control; oligomeric assembly
Issue or Number:11
PubMed Central ID:PMC7147533
Record Number:CaltechAUTHORS:20191101-145506688
Persistent URL:
Official Citation:Alison J. Inglis, Katharine R. Page, Alina Guna, Rebecca M. Voorhees, Differential Modes of Orphan Subunit Recognition for the WRB/CAML Complex, Cell Reports, Volume 30, Issue 11, 2020, Pages 3691-3698.e5, ISSN 2211-1247,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99627
Deposited By: Tony Diaz
Deposited On:01 Nov 2019 22:13
Last Modified:15 Feb 2022 23:32

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