Mechanisms for quality control of misfolded transmembrane proteins

Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Biochimica et Biophysica Acta (Impact Factor: 4.66). 11/2011; 1818(4):1108-14. DOI: 10.1016/j.bbamem.2011.11.007
Source: PubMed


To prevent the accumulation of misfolded and aggregated proteins, the cell has developed a complex network of cellular quality control (QC) systems to recognize misfolded proteins and facilitate their refolding or degradation. The cell faces numerous obstacles when performing quality control on transmembrane proteins. Transmembrane proteins have domains on both sides of a membrane and QC systems in distinct compartments must coordinate to monitor the folding status of the protein. Additionally, transmembrane domains can have very complex organization and QC systems must be able to monitor the assembly of transmembrane domains in the membrane. In this review, we will discuss the QC systems involved in repair and degradation of misfolded transmembrane proteins. Also, we will elaborate on the factors that recognize folding defects of transmembrane domains and what happens when misfolded transmembrane proteins escape QC and aggregate. This article is part of a Special Issue entitled: Protein Folding in Membranes.

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Available from: Scott A Houck, Jun 03, 2014
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    • "The non-native TMD caused CD8 TMD* to be localised to the ER and targeted for degradation through the ubiquitin-proteasome system. This sequence, derived from the fourth TMD of PLP, contains five weakly polar residues and one highly polar residue that could potentially act as signals for ER localisation and ERAD (Houck and Cyr, 2011;Ng et al., 2012). In addition, residues located between the transmembrane and cytosolic or luminal domains might influence the behaviour of integral membrane proteins, and thus defects at the TMD junctions could also contribute to the recognition of CD8 TMD* by the ERQC machinery. "
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    ABSTRACT: Clearance of misfolded proteins from the endoplasmic reticulum (ER) is mediated by the ubiquitin-proteasome system in a process known as ER-associated degradation (ERAD). The mechanisms through which proteins containing aberrant transmembrane domains are degraded by ERAD are poorly understood. To address this question, we generated model ERAD substrates based on CD8 with either a non-native transmembrane domain but a folded ER luminal domain (CD8(TMD*)), or the native transmembrane domain but a misfolded luminal domain (CD8(LUM*)). Whilst both chimeras were degraded by ERAD, we found that the location of the folding defect determined the initial site of ubiquitination. Ubiquitination of cytoplasmic lysine residues was required for the extraction of CD8(TMD*) from the ER membrane during ERAD, whilst CD8(LUM*) continued to be degraded in the absence of cytoplasmic lysines. Cytoplasmic lysines were also required for degradation of an additional ERAD substrate containing an unassembled transmembrane domain, and when a non-native transmembrane domain was introduced into CD8(LUM*). Our results suggest that proteins with defective transmembrane domains are removed from the ER via a specific ERAD mechanism that depends upon ubiquitination of cytoplasmic lysines.
    Preview · Article · Oct 2015 · Journal of Cell Science
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    • "Alternatively , the presence of a charged residue ( Asp ) inside the hydrophobic membrane helix could destabilize the protein , making it more difficult to be integrated in the lipid bilayer . This could explain the lower accumulation of the protein : membrane proteins that have folding problems are typically degraded by the cellular quality control system ( Nagy and Sanders , 2004 ; Houck and Cyr , 2012 ) . While the localization of the G40D GDU1 protein was not dramatically changed in N . "
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    ABSTRACT: Intracellular amino acid transport across plant membranes is critical for metabolic pathways which are often split between different organelles. In addition, transport of amino acids across the plasma membrane enables the distribution of organic nitrogen through the saps between leaves and developing organs. Amino acid importers have been studied for more than two decades, and their role in this process is well-documented. While equally important, amino acid exporters are not well-characterized. The over-expression of GDU1, encoding a small membrane protein with one transmembrane domain, leads to enhancement of amino acid export by Arabidopsis cells, glutamine secretion at the leaf margin, early senescence and size reduction of the plant, possibly caused by the stimulation of amino acid exporter(s). Previous work reported the identification of suppressor mutations of the GDU1 over-expression phenotype, which affected the GDU1 and LOG2 genes, the latter encoding a membrane-bound ubiquitin ligase interacting with GDU1. The present study focuses on the characterization of three additional suppressor mutations affecting GDU1. Size, phenotype, glutamine transport and amino acid tolerance were recorded for recapitulation plants and over-expressors of mutagenized GDU1 proteins. Unexpectedly, the over-expression of most mutated GDU1 led to plants with enhanced amino acid export, but failing to display secretion of glutamine and size reduction. The results show that the various effects triggered by GDU1 over-expression can be dissociated from one another by mutagenizing specific residues. The fact that these residues are not necessarily conserved suggests that the diverse biochemical properties of the GDU1 protein are not only born by the characterized transmembrane and VIMAG domains. These data provide a better understanding of the structure/function relationships of GDU1 and may enable modifying amino acid export in plants without detrimental effects on plant fitness.
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    • "Accordingly, it is likely that the cell has developed mechanisms of quality control to ensure proper interaction and integration of TM sequences during membrane protein biogenesis. With only a few exceptions (Houck and Cyr, 2012; Lemberg, 2013) little is known if or how intra-membrane assembly steps are linked to mechanisms of cellular quality control in membrane protein biogenesis or if membrane integration itself is scrutinized. "
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    ABSTRACT: 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.
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