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Guiding Tail-Anchored Membrane Proteins to the ER in a Chaperone Cascade

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Guiding Tail-Anchored Membrane Proteins to the ER in a Chaperone Cascade JBC Papers in Press. Published on October 1, 2019 as Manuscript REV119.006197 The latest version is at http://www.jbc.org/cgi/doi/10.1074/jbc.REV119.006197 Guiding Tail-anchored Membrane Proteins to the ER In a Chaperone Cascade Shu-ou Shan* Division of Chemistry and Chemical Engineering, California Institute of Technology 1200 E. California Blvd., Pasadena, CA 91125 Running title: chaperones guide tail-anchored protein targeting *To whom correspondence should be addressed. Phone: 626-395-3879. Fax: 626-568-9430. E- mail: [email protected] Downloaded from Key words: chaperone, membrane proteins, tail-anchored protein, Hsp70, protein targeting, ATPases http://www.jbc.org/ at CALIFORNIA INSTITUTE OF TECHNOLOGY on October 2, 2019 1 ABSTRACT homeostasis in the cell. Before arrival at the Newly synthesized integral membrane appropriate membrane destination, newly proteins must traverse the aqueous cytosolic synthesized membrane proteins must traverse environment before arrival at their membrane the cytosol and, in some cases, multiple other destination and are prone to aggregation, aqueous cellular compartments where misfolding, and mislocalization during this improper exposure of their transmembrane process. The biogenesis of integral domains (TMDs) will lead to rapid and membrane proteins therefore poses acute irreversible aggregation. In addition, the challenges to protein homeostasis within a degeneracy of TMD-lipid interactions poses cell and requires the action of effective challenges to the fidelity of their insertion at molecular chaperones. Chaperones that the appropriate biological membrane, Downloaded from mediate membrane protein targeting not only especially in eukaryotic cells that contain need to protect the nascent transmembrane multiple membrane-enclosed organelles. The domains from improper exposure in the proper localization and folding of membrane cytosol, but also to accurately select client proteins therefore relies critically on http://www.jbc.org/ proteins and actively guide their clients to the molecular chaperones, which not only protect appropriate target membrane. The nascent membrane proteins from off-pathway mechanisms by which cellular chaperones interactions but also actively guide them to work together to coordinate this complex the correct biological membrane. The process are only beginning to be delineated. mechanism by which the cellular chaperone at CALIFORNIA INSTITUTE OF TECHNOLOGY on October 2, 2019 Here we summary recent advances in studies network overcomes these challenges during of the tail-anchored membrane protein (TA) membrane protein biogenesis remains an targeting pathway, which revealed a network outstanding question. of chaperones, cochaperones, and targeting In the past decade, an increasing factors that together drive and regulate this number of factors have been described that essential process. This pathway is emerging represent components of multiple, distinct as an excellent model system to decipher the protein targeting pathways that deliver mechanism by which molecular chaperones nascent membrane proteins to diverse overcome the multiple challenges during organelles such as the endoplasmic reticulum post-translational membrane protein (ER), mitochondria, and peroxisomes (1-6). biogenesis and to gain insights into the One of these pathways, the guided entry of functional organization of multi-component tail anchored protein (GET) pathway, has chaperone networks. been studied at exquisite mechanistic detail. –––––––––––––––––––––––––––––––––––– This review will summarize recent advances Generation and maintenance of a in our understanding of the GET pathway, functional proteome requires the proper with a focus on a hierarchical chaperone folding, assembly, and localization of all the network found in this pathway that suggest cellular proteins. Integral membrane proteins sophisticated solutions to the challenges of comprise over 30% of the proteins encoded membrane protein biogenesis as well as new by the genome and mediate numerous questions about the role and mechanisms of essential cellular processes including molecular chaperones during this process. molecular transport, energy generation, signaling, and cell-to-cell communication. Diverse targeting pathways accommodate Compared to soluble proteins, the biogenesis membrane proteins with distinct TMD of integral membrane proteins poses locations. particularly acute challenges to protein 2 Diverse pathways mediate the targeting of arrow a; (11)). In addition, the SND genes are nascent membrane proteins to the ER, via synthetically lethal with the GET genes (13). which proteins enter the endomembrane These observations suggest that the SND system in eukaryotic cells. Despite being components provide a backup system for the overly simplistic, it has been useful to SRP and GET pathways to deliver membrane conceptualize the multitude of targeting proteins with relatively downstream TMDs. mechanisms in terms of the needs of Analogous diversity is observed with membrane proteins with distinct TMD translocases at the ER membrane: insertion of locations. For example, most membrane some SRP-dependent membrane proteins and proteins harboring a TMD near the N- less hydrophobic TAs are dependent on the terminus are recognized by the universally ER membrane protein complex (EMC) (Fig. Downloaded from conserved signal recognition particle (SRP) 1; (15-17)). In addition, Snd2/Snd3 as soon as their first TMD emerges from the genetically and physically interacts with exit tunnel of the translating ribosome. Sec72p(13), a component of the post- Ribosome profiling work in yeast further translational Sec62/63/71/72 translocase http://www.jbc.org/ suggested that SRP can engage ribosomes conserved across eukaryotic even earlier, before the targeting signals on organisms(18,19). The diversity and the nascent polypeptide are translated(7). Via redundancy of targeting and translocation interaction with the SRP receptor, SRP machineries are thought to provide a robust delivers translating ribosomes to the Sec61p network that accommodates the targeting at CALIFORNIA INSTITUTE OF TECHNOLOGY on October 2, 2019 translocase at the ER membrane (or the needs of diverse membrane proteins with SecYEG translocase at the bacterial plasma different TMD location, topology, and charge membrane), often before an additional 60- distribution. 100 residues of the nascent protein is At the other extreme is the class of synthesized (Fig 1, left path; (8-12)). The tail-anchored membrane proteins (TAs) strictly co-translational nature of the SRP whose TMD is near the C-terminus (Fig. 1, pathway ensures that the nascent TMDs are right path). TAs comprise up to 5% of the effectively shielded by proteinaceous eukaryotic membrane proteome and mediate environments in either the SRP or the Sec61p diverse cellular processes including protein (or SecYEG) complex, thus minimizing translocation across organellar membranes, exposure to the aqueous cytosolic vesicle fusion, apoptosis, and protein quality environment during their biogenesis control(2,20-22). As the C-terminal TMD is Much less is known about the obscured by the ribosome during translation, targeting of membrane proteins harboring it was predicted early on that TAs undergo internal TMDs (Fig. 1, middle path). A obligatorily post-translational mechanisms of genetic screen identified three genetically targeting(22). The past decade has witnessed linked SND (for SRP-independent targeting) the discovery of several pathways that proteins, Snd1 in the cytosol and Snd2 and mediate the targeted delivery and insertion of Snd3 at the ER membrane, whose loss led to TAs, including the GET-, SND-, and EMC- mislocalization of this class of proteins(13). dependent pathways (Fig. 1; More recently, the human orthologue of yeast (2,6,13,16,20,21,23)). The GET pathway, Snd2 has been described(14). Nevertheless, which targets relatively hydrophobic TAs to localized ribosome profiling data suggested the ER, is especially well studied. This that SRP is responsible for the cotranslational pathway is also remarkably conserved among ER-localization of most membrane proteins eukaryotic cells: all the components in the containing internal TMDs (Fig. 1, dashed yeast GET pathway have orthologues or 3 functional homologs in mammalian cells. facilitates TA transfer from Sgt2 to Get3 (Fig. The readers are referred to (2,6,20,21) for 2, steps 5-6;(30)). In mammalian cytosol, the comprehensive reviews of the GET pathway C-terminal part of the BAG6 complex and the targeting of tail-anchored proteins in (comprised of BAG6, TRC35 and UBL4A) general. Here, I will focus on the works that was shown to be structurally and functionally uncovered and characterized a multi- homologous to Get4/5 and facilitates TA component chaperone system required for the loading onto TRC40 from SGTA, the biogenesis of this essential class of mammalian Sgt2 homologue (29,31,32). membrane proteins. Thus, the substrate loading mechanism via the Sgt2-to-Get3 transfer is conserved among A chaperone cascade guides TAs to the ER. eukaryotic cells. Downloaded from Components of the GET pathway Despite these advances, how newly were initially identified through biochemical synthesized TAs are captured by Sgt2 reconstitutions and genetic interaction remained a long standing puzzle. Purified analyses of the secretory pathway in yeast. Sgt2 is ineffective in capturing TAs in the http://www.jbc.org/ Work in rabbit reticulocyte lysate identified a soluble form, and attempts to directly
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