Protein Degradation: BAGging Up the Trash

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Current biology: CB (Impact Factor: 9.57). 09/2011; 21(18):R692-5. DOI: 10.1016/j.cub.2011.08.018
Source: PubMed


Cells efficiently uncover and degrade proteins that are misfolded. However, we know very little about what cells do to protect themselves from mislocalized proteins. A new study reveals a novel quality control pathway that recognizes and degrades secretory pathway proteins that have failed to target to the endoplasmic reticulum.

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    • "Hydrophobic amino acids are typically buried within the tertiary structure of a protein, and their inappropriate exposure can be exploited by cellular quality control components as an indicator of misfolding (Buchberger et al., 2010). The contiguous stretches of hydrophobic amino acids that characterise integral membrane proteins provide a particularly extreme and aggregation-prone indicator of misfolding when such polypeptides mislocalise to the cytosol (Ast and Schuldiner, 2011; Leznicki et al., 2013; Rodrigo- Brenni and Hegde, 2012). For membrane proteins entering the eukaryotic secretory pathway, their signal recognition particle (SRP)-dependent delivery to the endoplasmic reticulum (ER) and subsequent co-translational integration by the Sec61 translocon effectively reduces the opportunity for any cytosolic exposure of their transmembrane domains. "
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    ABSTRACT: Hydrophobic amino acids are normally shielded from the cytosol and their exposure is often used as an indicator of protein misfolding to enable the chaperone mediated recognition and quality control of aberrant polypeptides. Mislocalised membrane proteins, or MLPs, represent a particular challenge to cellular quality control, and in this study membrane protein fragments have been exploited to study a specialised pathway that underlies the efficient detection and proteasomal degradation of MLPs. Our data show that the BAG6 complex and SGTA compete for cytosolic MLPs via recognition of their exposed hydrophobicity, and suggest that SGTA acts to maintain these substrates in a non-ubiquitinated state. Hence, SGTA may counter the actions of BAG6 to delay the ubiquitination of specific precursors and thereby increase their opportunity for successful post-translational delivery to the endoplasmic reticulum. However, when SGTA is overexpressed the normally efficient removal of aberrant MLPs is delayed, increasing their steady state level and promoting aggregation. Our data suggest that SGTA regulates the cellular fate of a range of hydrophobic polypeptides should they become exposed to the cytosol.
    Preview · Article · Sep 2014 · Journal of Cell Science
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    • "On the basis of these studies, a viable working hypothesis is that the BAG6-complex can recognize a range of “hydrophobic” substrates located in the cytosol and provide a sorting step that ensures they are correctly assigned to appropriate down stream effectors. These effectors may either enable the subsequent delivery of substrates to the ER for membrane insertion (via TRC40) or facilitate their ubiquitination and degradation at the proteasome (via components of the ubiquitin proteasome system) [30], [32]. In this study we have investigated the importance of the N-terminal UBL domain (∼ residues 17 to 88) and C-terminal BAG domain (∼ residues 1049 to 1105) of the BAG6 protein for binding to SGTA and two tail-anchored protein substrates. "
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    ABSTRACT: The BAG6 protein is a subunit of a heterotrimeric complex that binds a range of membrane and secretory protein precursors localized to the cytosol, enforcing quality control and influencing their subsequent fate. BAG6 has an N-terminal ubiquitin-like domain, and a C-terminal Bcl-2-associated athanogene domain, separated by a large central proline-rich region. We have used in vitro binding approaches to identify regions of BAG6 important for its interactions with: i) the small-glutamine rich tetratricopeptide repeat-containing protein alpha (SGTA) and ii) two model tail-anchored membrane proteins as a paradigm for its hydrophobic substrates. We show that the BAG6-UBL is essential for binding to SGTA, and find that the UBL of a second subunit of the BAG6-complex, ubiquitin-like protein 4A (UBL4A), competes for SGTA binding. Our data show that this binding is selective, and suggest that SGTA can bind either BAG6, or UBL4A, but not both at the same time. We adapted our in vitro binding assay to study the association of BAG6 with an immobilized tail-anchored protein, Sec61β, and find both the UBL and BAG domains are dispensable for binding this substrate. This conclusion was further supported using a heterologous subcellular localization assay in yeast, where the BAG6-dependent nuclear relocalization of a second tail-anchored protein, GFP-Sed5, also required neither the UBL, nor the BAG domain of BAG6. On the basis of these findings, we propose a working model where the large central region of the BAG6 protein provides a binding site for a diverse group of substrates, many of which expose a hydrophobic stretch of polypeptide. This arrangement would enable the BAG6 complex to bring together its substrates with potential effectors including those recruited via its N-terminal UBL. Such effectors may include SGTA, and the resulting assemblies influence the subsequent fate of the hydrophobic BAG6 substrates.
    Full-text · Article · Mar 2013 · PLoS ONE
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    ABSTRACT: Development of a fertilized human egg into an average sized adult requires about 29 trillion cell divisions, thereby producing enough DNA to stretch to the Sun and back 200 times (DePamphilis and Bell, 2011)! Even more amazing is the fact that throughout these mitotic cell cycles, the human genome is duplicated once and only once each time a cell divides. If a cell accidentally begins to re-replicate its nuclear DNA prior to cell division, checkpoint pathways trigger apoptosis. And yet, some cells are developmentally programmed to respond to environmental cues by switching from mitotic cell cycles to endocycles, a process in which multiple S phases occur in the absence of either mitosis or cytokinesis. Endocycles allow production of viable, differentiated, polyploid cells that no longer proliferate. What is surprising is that among the 516 (Manning et al., 2002) to 557 (BioMart web site) protein kinases encoded by the human genome, only eight regulate nuclear DNA replication directly. These are Cdk1, Cdk2, Cdk4, Cdk6, Cdk7, Cdc7, Checkpoint kinase-1 (Chk1), and Checkpoint kinase-2. Even more remarkable is the fact that only four of these enzymes (Cdk1, Cdk7, Cdc7, and Chk1) are essential for mammalian development. Here we describe how these protein kinases determine when DNA replication occurs during mitotic cell cycles, how mammalian cells switch from mitotic cell cycles to endocycles, and how cancer cells can be selectively targeted for destruction by inducing them to begin a second S phase before mitosis is complete.
    Full-text · Article · Sep 2012 · Frontiers in Physiology
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