Article

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

ABSTRACT

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.
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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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    • "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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