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Yu Cao Editor Advances in Membrane Proteins Building, Signaling and Malfunction Advances in Membrane Proteins Yu Cao Editor Advances in Membrane Proteins Building, Signaling and Malfunction Editor Yu Cao Department of Orthopaedics and Institute of Precision Medicine, Shanghai Key Laboratory of Orthopaedic Implant Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Shanghai, China ISBN 978-981-13-9076-0    ISBN 978-981-13-9077-7 (eBook) https://doi.org/10.1007/978-981-13-9077-7 © Springer Nature Singapore Pte Ltd 2019 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Acknowledgement This book is supported by the National Key Research and Development Program of China (2017YFC1001303 and 2018YFC1004704), NSFC-CAS Joint Fund for Research Based on Large-Scale Scientific Facilities (U1632132), and SHIPM-pi fund No JY201804 from Shanghai Institute of Precision Medicine, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine v Contents Lipid Homeostasis on Cell Membrane����������������������������������������������������������    1 Xian-Cheng Jiang A Historical Perspective of G Protein-­Coupled Receptor Structural Biology ��������������������������������������������������������������������������   31 Yang Chen, Ying Xia, and Yu Cao Membrane Proteins as Targets for Biological Drugs������������������������������������   49 Vanita D Sood and Alec W Gross Cell Adhesion Molecules����������������������������������������������������������������������������������   67 Xiajing Tong and Yan Zou The Biosynthesis and Folding of Oily Peptide Chains����������������������������������   85 Kai Li and Shi-Qing Cai Mechanism of Quality Control of Nascent Membrane Proteins ����������������  111 Zai-Rong Zhang vii Lipid Homeostasis on Cell Membrane Xian-Cheng Jiang Cell membrane is only a few nanometers in width (Andersen and Koeppe 2007) The lipid composition of cell membranes has a distinct outer versus inner polarity The exoplasmic side is enriched with phosphatidylcholine (PC) and sphingomyelin, whereas cytoplasmic side of the plasma membrane is enriched with phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidic acid (PA) (Bretscher 1972; van Meer 2011) In addition, the lipids of the membranes not evenly distributed because of the existing of lipid rafts and other structures (Sezgin et  al 2017) In this Chapter, we will discuss biosynthesis phospholipid, SM, and cholesterol, and their impact on cell membrane Phospholipid Biosynthesis (Kennedy Pathway) Phospholipids, 70% of which are PCs, make up the major lipids in cellular membranes (van Meer et al 2008; Yamashita et al 1997; Schlame et al 2000) Using acyl-CoAs as donors, phospholipids are formed from glycerol-­3-­phosphate (G3P) by the Kennedy pathway (also called the de novo pathway) (Kennedy and Weiss 1956) Biosynthesis of Phosphatidic Acid (PA) In the Kennedy pathway of phospholipid biosynthesis, lyso-PA (LPA) is first formed from Glycerol-3-phosphate (G3P) by G3P acyltransferases (GPATs) G3P is the product of glycolysis of glucose (Fig. 1) So far, four mammalian GPATs have been X.-C Jiang (*) SUNY Downstate Medical Center, Brooklyn, NY, USA e-mail: Xian-Cheng.Jiang@downstate.edu © Springer Nature Singapore Pte Ltd 2019 Y Cao (ed.), Advances in Membrane Proteins, https://doi.org/10.1007/978-981-13-9077-7_1 X.-C Jiang Fig 1  Kennedy pathway for phospholipid biosynthesis identified (Shindou and Shimizu 2009) Further, LPA is converted to PA by LPAATs, which have three isoforms currently (Shindou et al 2013) PA is a cone-shaped lipid that is needed to form negative curvature in cell membrane cytoplasmic leaflet, thus, facilitating the formation of the hemifusion intermediates required for the fusion of two membranes (Chernomordik and Kozlov 2005) PA is an important intermediate metabolite of all membrane phospholipids, including PC, PE, PS, PI (Fig.  1) and its phosphorylated derivatives (e.g., PIP2) Besides its metabolic contribution to membrane biogenesis, PA as well as its precursor LPA is an important signaling lipid Biosynthesis of PIs The condensation of PA and CTP forms CDP-diacylglycerol (CDP-DAG), the key component of biosynthesis of all phospholipids (Liu et al 2014) (Fig. 1) The PI biosynthesis is catalyzed by phosphatidylinositol synthase and is involved CDPDAG and L-myo-inositol (Fischl et al 1986) Phosphorylated derivatives of PI is a family of acidic phospholipids embedded in plasma membrane PI makes up approximately 10–20% of total cellular phospholipids (Hasegawa et al 2017) and they are localized at cytosolic leaflet of plasma membranes and they can recruit effector to membranes to modulate signaling events and plasma membrane dynamics (Tsujita and Itoh 2015; Schink et al 2016) Lipid Homeostasis on Cell Membrane Biosynthesis of PS In mammalian cells, PS is biosynthesized by PS synthase in a base-exchange manner (Kong et al 2017) However, in bacteria, PS is synthesized under PS synthase activity in a CDP-DAG-dependent manner (Fig. 1) There are two locations for PS biosynthesis, one is on cell endoplasmic reticulum (ER) and one is on a specific domain of mitochondria-associated membrane PS synthase I catalyzes the exchange reaction of L-serine with PC, whereas, PS synthase II catalyzes the exchange reaction of L-serine with PE (Arikketh et al 2008; Bergo et al 2002) Both PS synthases share 30% homology (Arikketh et al 2008; Bergo et al 2002) Biosynthesis of PE Mammalian cells have two pathways for PE biosynthesis: the PS  decarboxylase (PSD) pathway (Percy et  al 1983) (Fig.  1) and the CDP-ethanolamine pathway (Kennedy and Weiss 1956) The former is located in the ER and latter is in the mitochondria PE, though small amount, can also be synthesized through a the activity of PS synthase II, in which the serine residue of PS is exchanged for ethanolamine (Sundler et al 1974) Biosynthesis of PC PC de novo biosynthesis is carried out by the Kennedy pathway (Kennedy and Weiss 1956) (Fig. 1) Choline enters the cell via choline transporters (Traiffort et al 2013) Choline is phosphorylated by ATP to phosphocholine via the cytosolic enzyme choline kinase (CK) upon entering the cell (Aoyama et al 2004) There is another pathway for PC biosynthesis, i.e the conversion of CTP and phosphocholine to CDP-choline through the catalysis of CTP:phosphocholine cytidylyltransferase (CT) (Lykidis et  al 1999) The CT activity is the rate-limiting one for PC synthesis (Choy et  al 1979) The CDP-choline:1,2-diacylglycerol choline phosphotransferase (CPT) catalyze the final reaction in the CDP-choline pathway (Henneberry and McMaster 1999) The endoplasmic reticulum (ER) membrane is tightly embedded these enzymes (Henneberry et al 2002) which transfer phosphocholine from CDP-choline to DAG thereby generating PC. In addition to that, PC also can be derived from  PE  in the liver (Sundler and Akesson 1975) There are three sequential methylation reactions, in which S-adenosylmethionine (AdoMet) is the methyl group donor, on PE to produce PC. The enzyme for the methylation is PE  N-methyltransferase (PEMT) (Vance 2014) The liver seems to be the only mammalian tissue that has PEMT protein or activity (Vance and Ridgway 1988), although a small amount of PEMT activity has been reported in adipocytes during X.-C Jiang differentiation (Cole and Vance 2010) In rodents, approximately 70% of PC is generated by the CDP-choline pathway with the remaining 30% of PC being generated by PEMT pathway (DeLong et al 1999) Phospholipid Remodeling (Non-Kennedy Pathway) Membrane phospholipids are important structural and functional components of cellular membranes Certain membrane phospholipids are also the precursors of various lipid mediators such as eicosanoids and platelet-activating factor (Fig. 2) (Ishii and Shimizu 2000) The localization of fatty acids on phospholipids is in an asymmetrical manner Polyunsaturated fatty acids (PUFAs) are mainly located at the sn-2 position PA, PC, PE, PS, and PI compositions are significantly differnet in each tissue and cell type (van Meer et al 2008; Yamashita et al 1997) Only the Kennedy pathway cannot explain the diversity and asymmetry in phospholipids Sixty years ago, Lands discovered phospholipid remodeling pathway (Lands’ Fig 2  Non-Kennedy pathway (Lands’ cycle) for phospholipid biosynthesis Identified LPLATs are shown in the left (Red) LPLATs may affect cellular functions such as membrane fluidity, curvature, signaling and storage of lipid mediators The details are shown in the text 116 Z.-R Zhang Fig 2  Basic steps of ER-associated degradation Substrate recognition is the first step during ERAD. A non-native protein substrate could be recognized by a subset of ERAD cofactors and/or membrane-anchored E3 ligases through misfolded cytosolic, membrane or ER luminal domain Once recognized, the substrate is polyubiquitinated by the E3 ligase and cognate E2 Ubiquitinated substrate is then recruited to a dislocation complex probably comprising E3 ligase, Derlins, p97 complex and p97-cofactors A critical step is the engagement of substrate with p97 through polyubiquitin chain; this results in substrate retrotranslocation through membrane powered by ATP hydrolysis catalyzed by the p97 Substrate extracted from membrane is then escorted by shuttling factors to the proteasome for degradation 2011) We therefore primarily focus on several major E3 ubiquitin ligase complexes involved in ERAD and describe how they achieve substrate recognition, ubiquitination, and retrotranslocation or extraction Studies in the budding yeast Saccharomyces cerevisiae lead to identification of two ER membrane localized RING-finger ubiquitin ligases, Hrd1 and Doa10, which mediate most majority of the protein degradation from the ER membrane (Mehrtash and Hochstrasser 2018; Carvalho et al 2006) The third ubiquitin ligase, Asi complex, has been recently identified to be localized in the inner nuclear membrane (INM), an extension of ER and outer nuclear membrane (ONM) (Khmelinskii et al 2014; Foresti et al 2014) Since the nuclear envelope complex divides the INM and ONM, INM contains a specific subset of resident proteins to fulfill its function Asi complex thus theoretically shows distinct substrate specificity from other ERAD E3 ligases (Mehrtash and Hochstrasser 2018) Mechanism of Quality Control of Nascent Membrane Proteins 117 Fig 3  Three branches of ERAD pathway Three classes of substrates are defined according to the location of misfolded domains The different types of substrates harbor misfolded lesions located in the ER lumen (ERAD-L), membrane (ERAD-M), or the cytosol (ERAD-C) All three ERAD branches could be used for membrane protein degradation from the ER. The red stars represent the misfolded domains or degrons on substrates Hrd1p in the yeast is mainly responsible for targeting ERAD-L and -M substrates for degradation The former includes misfolded soluble proteins, and transmembrane protein with misfolded region within the luminal domain The ERAD-M substrates encompass membrane proteins with misfolded transmembrane region In human, there are two homologs of Hrd1p, Hrd1 and gp78, which show distinct yet overlapped substrate specificity TEB4 (or MARCH6) is the mammalian homolog of the yeast Doa10, main ubiquitin ligase for degrading ERAD-C substrates (Hirsch et al 2009) In addition to Hrd1 and gp78, the E3 ligases involved in mammalian ERAD also include TRC8, RMA1, RNF170, RNF145, RFP2, and TMEM129 Since dozens of ligases are reported to be resident in ER membrane (Neutzner et al 2011), others may function in the ERAD pathways and await further investigation Substrate Recognition How membrane proteins enter the degradation pathway on ER membrane? Specific selection or triage by quality control factors decides the degradative or non-­ degradative fate of a given protein While a limited number of proteins fail to achieve native conformation, most majority of proteins are mature and relatively stable proteins and perform housekeeping or regulatory functions More importantly, maturing proteins or folding intermediates actually adopt non-native conformations which should escape being recognized by quality control factors Therefore, substrate recognition with high fidelity is the major yet challenging task in protein quality control (Shao and Hegde 2016) If the recognition factors fail to engage misfolded proteins, they would form protein aggregates that show toxic effects to cell and organism, evidenced by many neurodegenerative diseases On the other hand, false selection and degradation would result in loss of function phenotype and diseases, as seen in degradation of CFTR mutants in the cystic fibrosis 118 Z.-R Zhang Protein quality control system must survey a large quantity of potential substrate peptides and discriminate terminally misfolded proteins from pool of native and/or folding species, and triage the former to the downstream events on the degradation pathway Of note, it is currently not known what are the actual conformations of folding and misfolded species, but they probably share similar features How quality control factors precisely distinguish these conformation-similar species has been the central problem and not been fully understood Yet, various studies in yeast provide clues how this client engagement may be accomplished Recognition of Membrane Proteins with Non-native ER Luminal Domain The Der3p or Hrd1p in baker’s yeast was initially discovered by studies on key steps in sterol synthesis and feedback-regulated mechanism of the HMG-CoA (3-hydroxy-­ 3-methylglutaryl-CoA) reductase (HMGR) The HMGR is an ER-resident integral membrane protein and a rate-limiting enzyme in the sterol or mevalonate biosynthetic pathway, catalyzing the reduction of HMG-CoA to mevalonic acid, the third step in the pathway When abundant sterol is present in the yeast cell, Hrd1p is able to recognize HMGR which subsequently undergoes rapid degradation so that the pathway is shut down by eliminating the protein and thus turning off its enzymatic activity (Wangeline et al 2017) The Hrd1p has N-terminal transmembrane region comprising transmembrane segments and a C-terminal cytosolic domains harboring RING-H2 motif, one of most common hallmarks of ubiquitin E3 ligases (Schoebel et al 2017) The cytosolic RING domain mainly catalyzes ubiquitination of substrates, in collaboration with E1, ubiquitin, E2 (Ubc7p), and Cue1p, a Ubc7p activator Hrd1p forms large and perhaps dynamic protein complex with a few accessory membrane proteins including Hrd3p, Der1p, Ubx2p and Usa1p, all of which play roles in the degradation of ERAD-L substrates (Carvalho et al 2006) Hrd3p (SEL1L in human) stabilizes Hrd1p which would otherwise undergoes automatic ubiquitination and rapid degradation in the absence of Hrd3p In mammals, however, Hrd1 is a stable protein even in the absence of SEL1L In general, ERAD-L substrates are detected by accessory factors of Hrd1 through features in misfolded or glycosylation status Hrd3p or SEL1L show conserved functions in recruiting ER luminal chaperons or lectins, such as Yos9p (OS9 and XTP3-B in mammals) (Christianson et al 2008; Denic et al 2006) These lectins recognize misfolded glycosylated proteins by binding specific sugar chains, and hand them over to Hrd1 complex through its interaction with Hrd3 or SEL1L.  Misfolded protein without N-linked glycan can be recruited by the ER luminal chaperon Kar2p (Bip in mammals) and transferred to Hrd1p complex (Okuda-Shimizu and Hendershot 2007) Alternatively, Hrd3p or SEL1L may directly recruit misfolded, non-glycosylated proteins and subsequently deliver them to the Hrd1 ubiquitin ligase complex (Fig. 4) Degradation of ERAD-L substrates also requires other accessory factors like Usa1p and its mammalian counterpart Herp They function as scaffold proteins for Mechanism of Quality Control of Nascent Membrane Proteins 119 Fig 4  Recognition of membrane protein with non-native ER luminal domain (ERAD-L) The misfolded luminal domain of a membrane protein can be recognized by lectin OS9 or XTP3B through binding to oligosaccharide chain Additionally, Bip is able to target non-glycosylated, misfolded peptide to downstream factors Sel1L. This leads to substrate association with the ubiquitin ligase Hrd1 The inset table summarized the components of the mammalian ERAD factors and their yeast counterparts the oligomerization of the Hrd1 and Hrd1 complex assembly Usa1p also mediates physical interactions between Hrd1p and Der1p Der1p has one paralog, Dfm1p, in yeast, and three orthologs in mammalian cells, namely Derlin1, Derlin2, and Derlin3 All five proteins are generally grouped and called the Derlins, which belongs to pseudo-rhomboid protease family as they are catalytically inactive Derlins are multi-spanning transmembrane proteins, and are able to directly bind ERAD-L substrate, as shown by cross-linking experiments (Mehnert et al 2014; Greenblatt et al 2011) It is conceivable that Derlins may be involved in substrate recognition and/or retrotranslocation In summary, recognition of ERAD-L substrates relies on presence of non-native luminal domain or specific glycan signals generated by chaperone network in the ER lumen The recognition mechanism seems to be conserved from the yeast to human  ecognition of Membrane Proteins with Misfolded Transmembrane R Domain Membrane protein substrates are routed for degradation by recognizing defective intramembrane lesions A typical feature of transmembrane domain is the hydrophobicity, allowing its spanning across biomembrane composed of hydrophobic 120 Z.-R Zhang lipid bilayer In aqueous compartments like the cytosol or ER lumen, misfolded proteins are believed to expose hydrophobic patches that can be recognized by quality control factors such as Bip and other heat shock proteins Contrary to this, defective transmembrane regions usually expose hydrophilic residues to the hydrophobic environment within lipid bilayer; these featured elements would lead to recognition by membrane anchored chaperones or ubiquitin ligases The first reported ERAD substrate of integral membrane protein is the HMG-­ CoA reductase (Hmg2p) in the yeast (Sato et al 2009) As mentioned in previous sections, accumulated sterol on ER membrane results in conformation change in the transmembrane domain (TMD) of Hmg2p; this leads to its recognition by the Hrd1p-mediated ERAD pathway While ERAD-L substrate needs almost many accessory factors to achieve efficient degradation, it has been reported that the ERAD-M substrates only requires Hrd1p and Hrd3p for ubiquitination and elimination The transmembrane region of Hrd1 primarily anchors the protein on the ER membrane, yet evidences showed that it could directly take part in substrate recognition There are many conserved polar residues within the transmembrane domain (TMD) of Hrd1p Studies from Hampton’s lab showed that these key residues mediates interaction between Hrd1p TMD and Hmg2p Mutation of these residues lead to decreased Hmg2p interaction with Hrd1p, largely reduced ubiquitination level of Hmg2p and defects in substrate degradation It was therefore suggested that the Hrd1p transmembrane domain directly recognizes misfolded regions of substrate within membrane lipid bilayer (Sato et al 2009) The Hrd1-Hrd3 complex is the main E3 ligase responsible for ubiquitination of most ERAD-M substrate in the yeast The other two E3 ligases, Doa10 and Asi complex, are also involved in certain ERAD-M substrates degradation Such substrate include the E2 conjugase Ubc6, transcription factor Spt1 and the NLS-fused sec61-2 mutant In mammals, Hrd1 (Synoviolin) and gp78 were discovered to be yeast Hrd1p homologues with low sequence identity in the transmembrane region However, gp78, but not Hrd1, was shown to be involved in regulated HMG-CoA Reductase (HMGR) degradation in mammalian cells Further study revealed that except gp78, ubiquitin ligases TRC8, RNF145 and TEB4 (Doa10  in mammals) also regulate HMGR degradation in a sterol-dependent manner Excess sterol induces structure change in the sterol-sending domain of HMGR which is subsequently recruited by the Insig1 or Insig2; either of these two proteins associates with gp78 and TRC8 and thus mediates interaction between E3 ligase and substrate in a sterol-dependent mode (Fig. 5) Recognition of Membrane Proteins with Misfolded Cytosolic Domain Transmembrane proteins with misfolded cytosolic domain expose lesions or degrons within their cytosolic regions or probably nucleoplasmic domains In yeast, these substrates (called ERAD-C substrates) are primarily recognized and degraded by Mechanism of Quality Control of Nascent Membrane Proteins 121 Fig 5  Recognition of membrane protein with membrane lesions Membrane resident ubiquitin ligase is able to directly contact substrate through their transmembrane domains In the case of sterol-dependent degradation of HMG-CoA reductase, excess sterol induces local conformation change within the transmembrane region of HMG-CoA reductase, resulting in recognition by gp78-associated Insig1 Doa10p-mediated pathway It is thus believed that Doa10 homolog in human, TEB4/MARCH6, may be also involved in the ubiquitination and degradation of this type of membrane proteins It is well known that misfolded cytosolic proteins usually expose non-native hydrophobic regions into the aqueous cytosolic compartment This leads to protein association with a wide array of molecular chaperons, such as Hsp90s, Hsp70s, and Hsp40s While these chaperons were initially found to be promoting protein folding, they also serve as adaptor proteins in recognizing terminally misfolded protein destined for degradation This function of chaperons applies to the misfolded cytosolic domain of transmembrane protein as well For example, Hsp40s, Ydj1p and Hlj1p, and Hsp70s, Ssa1, are shown to interact with misfolded domain of a few ERAD-C substrates and mediate their binding to Doa10p for ubiquitination (Nakatsukasa et al 2008) (Fig. 6) CHIP-Hsc70 is another pair of E3-chaperone to co-work in a similar manner for mediating ubiquitination of well-characterized misfolded membrane protein CFTR (Meacham et al 2001) Amphipathic helix is another feature of many Doa10 substrate Typical examples include degrons from Deg1, DegA/B, and CL1 Doa10p may recognize the hydrophobic surface of the amphipathic helices, because disruption of these hydrophobic surface impairs substrate degradation In certain cases, mammalian Hrd1 is able to interact with substrate through the amphipathic helix (Mehrtash and Hochstrasser Fig 6  Recognition of membrane proteins with cytosolic lesions Misfolding of the cytosolic domain of membrane protein causes chaperon Hsp70/40 to bind to the substrate and to deliver it to ubiquitin ligase Doa10p which promotes substrate ubiquitination and degradation 122 Z.-R Zhang 2018) A typical example is the Sgk1 which is a short-lived protein anchored on the ER membrane through an amphipathic motif Hrd1 mediates its degradation by recognizing the hydrophobic element in the motif and promoting its ubiquitination together with E2 enzymes Ube2G2 and Ube2j1 (Arteaga et al 2006) Mammalian Hrd1 has unique proline-rich domain (PRD) within cytosolic region, which is intrinsically disordered and plays important parts in recognizing substrates Membrane protein substrates recruited through the Hrd1 PRD domain include amyloid precursor protein (APP), Parl-R, CREBH, and many others (Wei et al 2018; Bhattacharya et al 2018; Omura et al 2006) Degradation of these membrane proteins is involved in many diseases Substrate Ubiquitination, E3 Ligase and Cofactors Most, if not all, ERAD-related E3 ligases bear the RING finger motif (really interesting new gene), and they all extrude into cytoplasmic space Hence, ERAD E3 ligases catalyze substrate ubiquitination at their cytosolic region This is generally achieved by classical E1-E2-E3 cascade, in which E3s are specialized membrane integrated ubiquitin ligases A few E2s are characterized to be involved in this process too; some of them are anchored on the membrane by a transmembrane helix or through binding to adaptor proteins (Hirsch et al 2009) As mentioned before, the RING motif of E3 is able to bind cognate E2 and stimulates E2’s discharging activity, releasing Ub for its conjugation to the lysine residues on substrate In yeast, primary E2s participating in ERAD are Ubc6p and Ubc7p, both of which are tethered on the ER membrane to function properly Ubc6p is a tail-­ anchored membrane protein bearing a C-terminus single transmembrane helix, which is inserted into ER membrane Ubc6p is a necessary component in Doa10-­ mediated ubiquitination and degradation pathway; it is also reported to be involved in ubiquitination catalyzed by Asi complex Ubc6p has two mammalian orthologs, Ube2j1 and Ubd2j2 (Wang et al 2009; Mueller et al 2008) Ube2j1 not only works together with Hrd1 to build polyubiquitin chain on ERAD substrates (Mueller et al 2008), but also tune and adjust ERAD capacity to meet prevailing needs by controlling level of ERAD enhancer proteins (Hagiwara et al 2016) The Ubc7p and its human homolog Ube2g2 have been extensively studied in terms of mode of activation and catalysis during the last decade In yeast, type-I membrane protein Cue1p integrates Ubc7p into the ER membrane-anchored Hrd1p complex through interactions mediated via a C-terminal Ubc7p-binding region (U7BR) The Cue1p contains not only the U7BR that activates Ubc7p’s activity (Bazirgan and Hampton 2008), but also the CUE domain which binds ubiquitin and thereby aligns growing ubiquitin chain with Ubc7p for ubiquitin chain elongation (von Delbruck et al 2016; Bagola et al 2013) Therefore, Cue1p is an important factor in Hrd1p complex for promoting ubiquitin chain formation and thus facilitating substrate degradation from the ER membrane Notably, except Cue1p, there are many other factors that can enhance ubiquitination of a certain range of substrates Mechanism of Quality Control of Nascent Membrane Proteins 123 Similar to Ubc7p, the mammalian Ube2g2 is recruited to the membrane through the Ube2g2-Binding Region (G2BR), which was found in the AUP1 and the ubiquitin ligase gp78 In general, E2-E3 binding is transient and quickly dissociates to release the empty E2 for recharging Ub handed over from E1~Ub This leads to multi-round E2-E3 assembly and rapid ubiquitin chain elongation, and thus builds polyubiquitin chain long enough for engagement with downstream factors such as p97 complex and proteasome (Deshaies and Joazeiro 2009) However, the unique G2BR allows gp78 to stably associate and stimulate Ube2g2, suggesting that G2BR binding region on Ube2g2 should be away from active site cysteine responsible for mediating Ub transfer This was confirmed by structural analysis which showed that the G2BR-Ube2g2 binding region lied in the “back-site” of the Ube2g2, opposite to the enzyme face containing the catalytic pocket for accepting and discharging Ub In addition to the G2BR, gp78 also bears a CUE domain that binds Ub chain and is shown to facilitate Ub chain elongation (Morito et al 2008) Ube2g2 forms ­oligomer Fig 7  Membrane protein ubiquitination by gp78 or Doa10p (a) The ubiquitin-conjugating enzyme Ube2g2 stably associates with gp78 through binding to the G2BR domain Oligomerization of gp78 might promote ubiquitin chain assembly on the active site of the Ube2g2, which can be transferred en bloc to substrate In addition, the CUE domain of gp78 is able to bind growing ubiquitin chain and further promotes chain elongation (b) During Doa10p-mediated ubiquitination, the E2 Ubc6p adds the first ubiquitin to the substrate, followed by ubiquitin chain elongation catalyzed by the E2 Ubc7p 124 Z.-R Zhang and assembles K-48 linked polyubiquitin chain onto its catalytic site, which is transferred to a lysine residue of a substrate en bloc (Li et al 2007) (Fig. 7a) In yeast, it was reported that both Ubc6p and Ubc7p are necessary for Doa10-­ mediated degradation Recent work suggested a sequential mechanism of ubiquitination catalyzed by Ubc6p, Ubc7p and Doa10p Ubc6p attaches mono-Ubiquitin to not only the lysine but also the Ser or The residues of the substrate The Ub moiety then acts as a primer for subsequent polyubiquitin chain elongation that is catalyzed by the Ubc7 (Weber et al 2016) (Fig. 7b) By this manner, Ubc6 may conjugate Ub on diverse amino acids and increase the number of modification sites within a substrate to enlarge the substrate range of Doa10  embrane Protein Retrotranslocation from ER Membrane, M Hrd1 in Yeast, Derlins As the proteasome mainly resides in the cytosolic and nuclear compartments outside the ER, misfolded ER proteins must exit the ER to be accessed by the degradation machinery Retrotranslocation is termed to describe protein movement from the ER lumen or membrane to the cytoplasm or nucleoplasm, an opposite process to nascent chain translocation through Sec61 translocon It is generally believed that protein retrotranslocaiton across membrane is mediated by proteinaceous protein-­ conduit channel(s) called retrotranslocon or dislocon In mammalian cells, some membrane proteins become ERAD substrate due to a misfolded or unassembled luminal domain; these include well-characterized T-cell receptor α chain (TCRα), CD3δ, and CD146 Although they all have cytosolic tail and transmembrane segment, the non-native luminal region is recognized by ERAD factors and is then retrotranslocated across ER membrane, followed by ubiquitination and engagement with cytosolic motor proteins that pull substrate out of ER (Burr et al 2013) This retrotranslocation mode is conceptually equivalent to the ERAD-L in the yeast For integral membrane protein with lesions in membrane and/ or cytosolic region, retrotranslocation may be initiated by extracting domains already existed in the cytosolic face of membrane The mechanism of action is analogous to the ERAD-M or ERAD-C in the yeast Membrane proteins degraded in this manner may include ENaC, CFTR-delF508, GluR, HMGR, and inositol 1,4,5-trisphosphate receptor (Fig. 8) For more than a decade, a few proteins have been proposed to serve as retrotranslocation channel, including Sec61, Derlins, and Hrd1 In yeast, evidences have indicated that Hrd1p is prominent candidate for such channel First, overexpression of Hrd1 bypasses the necessity of other accessory factors in the Hrd1p complex, including Usa1p, Hrd3p, and Der1p, for the degradation of ERAD-L substrates Second, site-specific crosslinking experiments showed that Hrd1p directly interacts with substrates through its transmembrane segments (Carvalho et al 2010) Third, purified Hrd1p alone reconstituted into proteoliposome promotes the Mechanism of Quality Control of Nascent Membrane Proteins 125 Fig 8  Different modes of membrane protein retrotranslocation (a) Single-spanning membrane protein with charged residues within the transmembrane segment can fully translocate into the ER lumen and then retrotranslocated like an ERAD-L substrate (Feige and Hendershot 2013) (b) Misfolded luminal domain of membrane protein might be recognized by ER chaperons and translocated out of ER membrane through a potential channel The cytosol-exposed protein is then ubiquitinated by E3 ligase and completely pulled out of membrane (c) Membrane proteins could be recognized and ubiquitinated in their cytosolic domain and then extracted through a protein-­ conducting channel before complete release into the cytosol r­etrotranslocation of ERAD-L substrate CPY∗ through membrane (Baldridge and Rapoport 2016; Stein et al 2014) These results strongly indicate that Hrd1 alone is able to mediate polypeptide movement across membrane to reach the cytosol (Wu and Rapoport 2018) Cryo-EM structure for Hrd1p-Hrd3p revealed that Hrd1p forms a dimer within the membrane with Hrd3p associated at luminal side Each Hrd1p protomer has eight transmembrane segments, six of which forms aqueous, funnel-like cavity; the potential conduit, however, is sealed at the end near the luminal side within the membrane (Schoebel et al 2017) (Fig. 9) What is the function of Hrd1p dimerization and how the sealed gate is opened or regulated are currently unknown The transmembrane domain of Hrd1p contains conserved residues which are also found in a few mammalian ubiquitin ligases including Hrd1, gp78, RNF145, and TRC8, suggesting that these transmembrane E3 ligases may also form aqueous channel to allow entry of substrate peptide Other accessory factors could facilitate protein retrotranslocation Der1p directly interacts with substrate using residues within its transmembrane segments and is required for the degradation of many ERAD-L substrates (Mehnert et al 2014) Mammalian Derlins are also shown to be involved in protein retrotranslocation (Greenblatt et al 2011) Whether the catalytic mechanism 126 Z.-R Zhang Fig 9  Cryo-EM structure of dimeric Hrd1p transmembrane domain shows a potential funnel-like channel (PDB entry 5V6P) (a) Top view of the Hrd1p transmembrane domain dimer from the cytosolic side Red circle denotes the position of the potential hydrophilic channel (b) Side view of the Hrd1p transmembrane domain Funnel-like protein-conducting channel was depicted as a conical frustum The shaded oval represents the sealed end or the luminal “gate” of the channel of Derlins is conserved is currently not known because mammals have expansion on genes of Derlin comprising Derlin1, Derlin2, and Derlin3 Apart from the peptide channel, p97/VCP (Cdc48 in yeast) is another essential factor involved in protein retrotranslocation p97 is a homohexameric AAA ATPase that hydrolyzes ATP and provides the driving force to overcome the energy barrier of lipid bilayer and pull or “segregate” the substrate protein from membrane p97 functions as a “segregase” and plays important roles in many cellular processes, along with a variety of cofactors recruited through p97/VCP-binding domains or motifs, such as UBX domain, SHP motif, VIM motif, and VBD domain In the process of ERAD, p97 cofactor dimeric Ufd-Npl4 complex recognizes ubiquitinated substrates through interacting with polyubiquitin chain attached on substrate by membrane anchored ubiquitin ligases p97/VCP also interacts with many other ERAD factors, including E3s (e.g., Hrd1, gp78), accessory factors (e.g., UbxD8, VIMP, Derlins, UbxD2), and deubiquitinases (e.g., Ataxin-3, YOD1) (Ernst et al 2009), establishing a hub to regulate retrotranslocation through modulating ubiquitination It has long been thought that p97/VCP segregates substrate from membrane or protein complex by threading the substrate peptide through the central pore of the p97 hexamer This now has been confirmed in recent in  vitro studies on yeast Cdc48p (Bodnar and Rapoport 2017; Blythe et al 2017) Substrate initially engages with Cdc48p though the polyubiquitin chain recognized by Ufd1-Npl4 complex; this permits translocation of peptide through the central pore of Cdc48p which hydrolyzes ATP and provides energy to progressively unfold substrate Notably, deubiquitinase Yod1 is necessary to shorten the long ubiquitin chain for allowing the substrate peptide to complete release from the Cdc48p into the cytosol Interestingly, ubiquitin chain is not necessary to be completely removed as partially trimmed ubiquitin chain is able to translocate through the central pore, along with substrate peptide, suggesting that the pore may be dynamic and wide sufficient to Mechanism of Quality Control of Nascent Membrane Proteins 127 simultaneously accommodate both substrate peptide and perhaps partially unfolded short ubiquitin chain Once membrane protein substrates are released from the p97/VCP and reached the cytosol, exposed hydrophobic segments can be chaperoned by some holdases such as BAG6 and SGT to maintain unfolded conformation and/or prevent aggregation (Wang et  al 2011; Xu et  al 2012) Delivering substrate to proteasome may require a collection of shuttling factors, such as Dsk2p (Ubiquilins in human) or Rad23p (hHR23A and hHR23B); they have both ubiquitin- and proteasome-­binding domain so that they are able to connect ubiquitinated substrate to the proteasome for ultimate proteolysis Although ERAD has been studied for a few decades and many factors have been identified, our understanding on membrane protein degradation is still limited For example, how transmembrane segments of multi-spanning membrane proteins are extracted from membrane remains largely obscure Since ERAD is important to maintain ER homeostasis, it is also not clear how ERAD capacity or 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Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Shanghai, China ISBN 97 8-9 8 1-1 3-9 07 6-0     ISBN 97 8-9 8 1-1 3-9 07 7-7  (eBook) https://doi.org/10.1007/97 8-9 8 1-1 3-9 07 7-7 .. .Advances in Membrane Proteins Yu Cao Editor Advances in Membrane Proteins Building, Signaling and Malfunction Editor Yu Cao Department of Orthopaedics and Institute of Precision Medicine,... adaptor protein TNFR type 1-associated DEATH domain protein (TRADD) to bind to the death domain, serving as a platform for subsequent 14 X.-C Jiang protein binding Following TRADD binding, three

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Mục lục

  • Acknowledgement

  • Contents

  • Lipid Homeostasis on Cell Membrane

    • Phospholipid Biosynthesis (Kennedy Pathway)

      • Biosynthesis of Phosphatidic Acid (PA)

      • Biosynthesis of PIs

      • Biosynthesis of PS

      • Biosynthesis of PE

      • Biosynthesis of PC

      • Phospholipid Remodeling (Non-Kennedy Pathway)

        • LPCAT1

        • LPCAT2

        • LPCAT3

        • LPCAT4

        • LPEAT1

        • LPEAT2

        • Phospholipids and Membrane

          • PA/LPA and Membrane

          • PIs and Membrane

          • PS and Membrane

          • PE and Membrane

          • PCs and Membrane

          • SM

            • SPT and Its Subunits

            • SMS Family

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