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Protein Folding and Quality Control in the Endoplasmic Reticulum Bertrand Kleizen and Ineke Braakman1

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Protein Folding and Quality Control in the Endoplasmic Reticulum Bertrand Kleizen and Ineke Braakman1 Protein folding and quality control in the endoplasmic reticulum Bertrand Kleizen and Ineke Braakman1 The endoplasmic reticulum (ER) is a highly versatile protein >100 mg/ml. In this gel-like protein matrix, chaperones factory that is equipped with chaperones and folding enzymes and folding enzymes are abundant, greatly outnumbering essential for protein folding. ER quality control guided by the newly synthesised substrates [8]. These folding fac- these chaperones is essential for life. Whereas correctly tors in general prevent aggregation and thereby allow folded proteins are exported from the ER, misfolded proteins more efficient folding of a large variety of proteins. In this are retained and selectively degraded. At least two main review, we highlight the latest advances in understanding chaperone classes, BiP and calnexin/calreticulin, are active how these chaperones and folding enzymes cooperate in in ER quality control. Folding factors usually are found in assisting protein folding and mediating quality control. complexes. Recent work emphasises more than ever that chaperones act in concert with co-factors and with each other. Co-translational and post-translational folding Addresses Mammalian secretory and membrane proteins are synthe- Department of Bio-Organic Chemistry 1, Utrecht University, sised and translocated into the ER by the ribosome/sec61 Padualaan 8, 3584 CH Utrecht, The Netherlands 1 translation/translocation machinery, of which various e-mail: [email protected] enlightening X-ray structures have recently been deter- mined [9,10]. During translation/translocation newly Current Opinion in Cell Biology 2004, 16:343–349 synthesised proteins immediately start to fold. Combin- ing these processes allows sequential folding which may This review comes from a themed issue on greatly enhance folding efficiency, especially of multi- Membranes and organelles Edited by Judith Klumperman and Gillian Griffiths domain proteins [11]. The immunoglobulin molecule with its heavy and light chains undergoes extensive Available online 20th June 2004 folding and assembly already during synthesis [12]. Another example is the ribosome-bound nascent chain 0955-0674/$ – see front matter ß 2004 Elsevier Ltd. All rights reserved. of the Semliki Forest virus capsid protease domain, which was shown to be folded and autoproteolytically active DOI 10.1016/j.ceb.2004.06.012 immediately after translocon exit, indicating that folding occurs co-translationally but after translocation [13]. Abbreviations Other proteins, on the other hand, need extensive CNX calnexin post-translational folding to acquire their proper native CRT calreticulin conformation. Envelope glycoprotein gp160 of HIV-1, for ER endoplasmic reticulum ERAD ER-associated degradation example, is synthesised within approximately five minu- FRET fluorescence resonance energy transfer tes, but resides for hours in the ER with no apparent HA hemagglutinin degradation [14]. The LDL receptor (LDL-R) also folds LDL-R LDL receptor after synthesis: it collapses into a compact structure with PDI protein disulfide isomerase non-native disulphide bonds and then continues to fold QC quality control UGGT UDP-glucose:glycoprotein glucosyltransferase into a less compact structure with native disulphide bonds [15]. Both gp160 and the LDL-R need extensive post- translational disulphide isomerisation to fold into the Introduction native structure. Thyroglobulin even folds via a high The endoplasmic reticulum (ER) has many functions, molecular weight complex, which first involves formation including lipid donation to other organelles (reviewed by of disulphide-linked aggregates that with time unfold and van Meer and Sprong in this issue), Ca2þ homeostasis [1], assemble into dimers [16]. Whereas some soluble proteins biogenesis of organelles [2], protein folding, quality con- fold relatively easily, others have more difficulty folding trol (QC) [3,4] and protein degradation. Although the and require more assistance from chaperones and folding native conformation of a protein lies encoded in its enzymes. primary amino acid sequence, the ER greatly enhances protein folding efficiency [5]. The ER is highly specia- Chaperones in complexes lised for folding: approximately one-third of all proteins in Previous studies that combined chemical cross-linking a eukaryotic cell are translocated into the ER [6]; the ER with immunoprecipitation suggested that chaperones act has unique oxidizing potential that supports disulphide on newly synthesised proteins in the context of a com- bond formation during protein folding [7]; and the ER plex. During folding of the homodimer thyroglobulin lumen is very crowded, with a protein concentration of (each subunit of which is 330 kD), the Hsp70 chaperone www.sciencedirect.com Current Opinion in Cell Biology 2004, 16:343–349 344 Membranes and organelles Table 1 Chaperone and folding enzyme complexes containing BiP. Family Protein Reference Related proteins not found in a BiP complex Hsp90 Grp94 [17–20,21,30] Hsp70/Hsp110 Grp170 [17,21] Lectin Calreticulin [18,20] Calnexin Lectin UGGT [21] Calnexin Co-chaperone ERdj3 [21] ERdj1, ERdj2, ERdj4, ERdj5 Oxidoreductase PDI [17,19,21] ERp19, ERp44, ERp46, ERp57, TMX, ERdj5 ERp72 [17,20,21] CaBP1 (P5) [21] Erp29 [19,21] PPIase Cyclophilin B [20,21] FKBP65 Several laboratories found multimeric chaperone and folding enzyme assemblies that interacted with proteins that fold in the ER. The redox protein family, which rapidly expands, includes important constituents of the BiP complex. BiP was present in a multimeric complex with Grp94, residues, creating a monoglucosylated glycan. CNX imme- Grp170 and the redox proteins PDI (protein disulfide diately binds to HA when 30 residues have entered the isomerase) and ERp72 [17]. The influenza virus hemag- ER lumen, suggesting that both glucosidases function in glutinin (HA) cross-linked in a 1:1 stoichiometry with the very close proximity to the translocon as well [24]. lectin chaperones calnexin (CNX) and calreticulin (CRT), but only with trace amounts of BiP. In the Immunoglobulin and HA are examples of proteins that absence of protein synthesis, CRT was found in complex exclusively bind BiP or CNX/CRT, respectively, whereas with BiP and Grp94, whereas CNX was not [18]. Several other proteins may need both for folding. When N- recent studies confirmed that an ensemble of chaperones glycans were located within the first 50 residues of and folding enzymes act on thryroglobulin [19], on slow influenza virus HA, CNX interacted with the glycopro- folding apolipoprotein B [20] and on unassembled immu- tein. When these N-terminal glycans were removed, noglobulin heavy chain [21] to assist folding. BiP and initial CNX binding was prevented and BiP interacted Grp94 were always present, whereas additional chaper- with the glycoprotein [25]. Which chaperone complex is ones and folding enzymes varied (Table 1). The BiP recruited is determined by the characteristics of the chaperone complex of unassembled immunoglobulin also folding protein. formed independently of synthesis, suggesting that it is an intrinsic ER chaperone complex [21]. The BiP chaperone complex How do chaperone complexes assist proteins in folding? Large-scale analysis of TAP-tagged proteins in yeast Is there a functional physical interaction between cha- implied that 78% of the studied proteins were in multi- perones, co-chaperones and folding enzymes? BiP has an protein complexes [22]. Because chaperones are notor- ATPase domain and a peptide-binding domain that co- iously ‘sticky’, they were part of too many of the ordinate repetitive cycles of ATP hydrolysis and ADP complexes and were therefore excluded from analysis. exchange, stimulating binding and release of the unfolded protein, respectively [26]. Co-chaperones, as BiP and calnexin: the first to act has been shown in detail for cytosolic and bacterial Mammalian BiP (Grp78) is one of the most abundant ER Hsp70s, influence the cycle by modulating ATP hydro- chaperones and is closely related to cytosolic Hsp70. lysis (J-proteins) or ADP exchange (e.g. Bag-1). Recently, Although the recent crystal structure of SecY suggests that several J-domain-containing partner proteins for BiP were the permeability barrier between the cytosol and the ER is identified: ERdj 1–5. ERdj3 indeed stimulated ATP a feature of the translocon alone, previous data demon- hydrolysis of BiP in vitro and was found in the BiP strated that BiP seals the pore at the ER lumenal side complex with unassembled heavy chain in vivo [21,27]. [10,23]. Because of its location, BiP can immediately interact with the unfolded nascent chain, and hence con- Although a specific nucleotide exchange protein for BiP tribute to the translocation of nascent chains into the ER. was identified in the mammalian ER, this protein, BAP, was not found in the BiP complex [28]. Two additional CNX is located near the translocon and can interact with nucleotide exchange factors were found for yeast BiP nascent chains of N-glycosylated proteins. A prerequisite (Kar2p), not only Sil1p but also Lhs1p, a Grp170 homo- for both CNX and CRT binding to newly synthesised logue with similarity to Hsp70s and Hsp110. Interest- glycoproteins is a sequential, initially co-translational, ingly, Lhs1p stimulates ADP exchange of Kar2p, whereas action by a-glucosidases I and II that trim two glucose Kar2p stimulates ATP hydrolysis of Lhs1p [29]. This Current Opinion in Cell Biology 2004, 16:343–349 www.sciencedirect.com Protein folding and quality control in the endoplasmic
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