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• W4220997051 abstract "The majority of human proteins function as part of multimeric protein complexes.Subunit stoichiometry in vivo is highly variable, and a significant fraction of the proteome arises from non-stoichiometric synthesis.The ubiquitin–proteasome system (UPS) can detect failures in complex assembly and target unassembled or incorrectly assembled complexes for degradation.Key cellular complexes such as hemoglobin, BTB (broad complex, Tramtrack, and Bric-à-brac) dimers, the proteasome, and the ribosome have recently been shown to undergo assembly quality control (AQC).AQC safeguards cellular function and health. The majority of human proteins operate as multimeric complexes with defined compositions and distinct architectures. How the assembly of these complexes is surveyed and how defective complexes are recognized is just beginning to emerge. In eukaryotes, over 600 E3 ubiquitin ligases form part of the ubiquitin–proteasome system (UPS) which detects structural characteristics in its target proteins and selectively induces their degradation. The UPS has recently been shown to oversee key quality control steps during the assembly of protein complexes. We review recent findings on how E3 ubiquitin ligases regulate protein complex assembly and highlight unanswered questions relating to their mechanism of action. The majority of human proteins operate as multimeric complexes with defined compositions and distinct architectures. How the assembly of these complexes is surveyed and how defective complexes are recognized is just beginning to emerge. In eukaryotes, over 600 E3 ubiquitin ligases form part of the ubiquitin–proteasome system (UPS) which detects structural characteristics in its target proteins and selectively induces their degradation. The UPS has recently been shown to oversee key quality control steps during the assembly of protein complexes. We review recent findings on how E3 ubiquitin ligases regulate protein complex assembly and highlight unanswered questions relating to their mechanism of action. Principles of protein complex synthesis and assemblyProteins are key effectors of all cellular processes. To carry out their biological roles, most proteins assemble into multimeric complexes of defined architecture and composition [1.Huttlin E.L. et al.Architecture of the human interactome defines protein communities and disease networks.Nature. 2017; 545: 505-509Crossref PubMed Scopus (761) Google Scholar]. Three fundamental steps are required to generate functional protein complexes: transcription, translation, and the folding and assembly of newly synthesized polypeptides into functional three‑dimensional structures. Protein folding starts in the ribosome exit tunnel, facilitated by a network of ribosome-associated chaperones [2.Balchin D. et al.In vivo aspects of protein folding and quality control.Science. 2016; 353: aac4354Crossref PubMed Scopus (736) Google Scholar], and 30% of proteins require further assistance from specialized chaperones to attain their biologically active conformation [2.Balchin D. et al.In vivo aspects of protein folding and quality control.Science. 2016; 353: aac4354Crossref PubMed Scopus (736) Google Scholar]. Misfolded or misassembled proteins are prone to cytotoxic aggregation, and defects in protein folding and assembly underlie conditions including aging, cancer, and neurodegeneration [3.Ellis R.J. Protein misassembly: macromolecular crowding and molecular chaperones.Adv. Exp. Med. Biol. 2007; 594: 1-13Crossref PubMed Scopus (113) Google Scholar,4.Hipp M.S. et al.Proteostasis impairment in protein-misfolding and -aggregation diseases.Trends Cell Biol. 2014; 24: 506-514Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar]. For protein complexes to form, newly-synthesized subunits must come together spatially and temporally, and develop inter-subunit interfaces while simultaneously avoiding interactions with unrelated cellular components. Assembly must additionally take place stoichiometrically and not generate potentially cytotoxic intermediates. To facilitate this process, organisms – most notably prokaryotes – organize functionally related genes into operons, and differentially express the open reading frames (ORFs) within the resulting mRNAs to match the stoichiometry in the final complex [5.Li G.W. et al.Quantifying absolute protein synthesis rates reveals principles underlying allocation of cellular resources.Cell. 2014; 157: 624-635Abstract Full Text Full Text PDF PubMed Scopus (756) Google Scholar, 6.Burkhardt D.H. et al.Operon mRNAs are organized into ORF-centric structures that predict translation efficiency.eLife. 2017; 6e22037Crossref Scopus (81) Google Scholar, 7.Chen J. et al.Pervasive functional translation of noncanonical human open reading frames.Science. 2020; 367: 1140-1146Crossref PubMed Scopus (310) Google Scholar]. A similar effect is achieved by genetic fusions between separate functional domains into single proteins, predominantly in yeast [8.Zhang X. Smith T.F. Yeast 'operons'.Microb. Comp. Genomics. 1998; 3: 133-140Crossref PubMed Scopus (27) Google Scholar]. Several post-transcriptional mechanisms further promote complex assembly. The mRNAs of functionally related proteins often colocalize in vivo [9.Pizzinga M. et al.Translation factor mRNA granules direct protein synthetic capacity to regions of polarized growth.J. Cell Biol. 2019; 218: 1564-1581Crossref PubMed Scopus (22) Google Scholar,10.Nair R.R. et al.Multiplexed mRNA assembly into ribonucleoprotein particles plays an operon-like role in the control of yeast cell physiology.eLife. 2021; 10e660050Crossref Scopus (5) Google Scholar], and nascent subunits frequently interact with their partners cotranslationally [11.Shiber A. et al.Cotranslational assembly of protein complexes in eukaryotes revealed by ribosome profiling.Nature. 2018; 561: 268-272Crossref PubMed Scopus (146) Google Scholar,12.Bertolini M. et al.Interactions between nascent proteins translated by adjacent ribosomes drive homomer assembly.Science. 2021; 371: 57-64Crossref PubMed Scopus (25) Google Scholar]. Interactions between nascent proteins can be further aided by assembly-guiding chaperones [13.Shieh Y.W. et al.Operon structure and cotranslational subunit association direct protein assembly in bacteria.Science. 2015; 350: 678-680Crossref PubMed Scopus (112) Google Scholar,14.Livneh I. et al.The life cycle of the 26S proteasome: from birth, through regulation and function, and onto its death.Cell Res. 2016; 26: 869-885Crossref PubMed Scopus (183) Google Scholar]. Despite these regulatory mechanisms, the assembly of protein complexes remains an intrinsically error-prone process, and nonstoichiometric subunit synthesis, as well as stochastic errors in assembly, continually generate protein orphans and defective protein complexes [15.McShane E. et al.Kinetic analysis of protein stability reveals age-dependent degradation.Cell. 2016; 167: 803-815Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 16.Mena E.L. et al.Dimerization quality control ensures neuronal development and survival.Science. 2018; 362: eaap8236Crossref PubMed Scopus (37) Google Scholar, 17.Harper J.W. Bennett E.J. Proteome complexity and the forces that drive proteome imbalance.Nature. 2016; 537: 328-338Crossref PubMed Scopus (136) Google Scholar]. Around half of all mammalian protein complexes are produced with at least one subunit synthesized in nonstoichiometric amounts [18.Ori A. et al.Spatiotemporal variation of mammalian protein complex stoichiometries.Genome Biol. 2016; 17: 47Crossref PubMed Scopus (65) Google Scholar], and ~10% of the nascent proteome is estimated to arise from nonstoichiometric synthesis or failed assembly [15.McShane E. et al.Kinetic analysis of protein stability reveals age-dependent degradation.Cell. 2016; 167: 803-815Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar]. Furthermore, the subunit stoichiometry of many eukaryotic complexes varies across cell types and throughout differentiation [18.Ori A. et al.Spatiotemporal variation of mammalian protein complex stoichiometries.Genome Biol. 2016; 17: 47Crossref PubMed Scopus (65) Google Scholar]. Subunit imbalances, particularly in the context of altered gene expression such as in stress and cancer, can generate cytotoxic species through subunit aggregation as well as by gain, or loss, of function [14.Livneh I. et al.The life cycle of the 26S proteasome: from birth, through regulation and function, and onto its death.Cell Res. 2016; 26: 869-885Crossref PubMed Scopus (183) Google Scholar,17.Harper J.W. Bennett E.J. Proteome complexity and the forces that drive proteome imbalance.Nature. 2016; 537: 328-338Crossref PubMed Scopus (136) Google Scholar].The stability of most proteins in vivo cannot be accurately predicted from factors such as mRNA half-life and protein abundance, and instead depends on post-translational events such as ubiquitination [15.McShane E. et al.Kinetic analysis of protein stability reveals age-dependent degradation.Cell. 2016; 167: 803-815Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar,19.Schwanhausser B. et al.Global quantification of mammalian gene expression control.Nature. 2011; 473: 337-342Crossref PubMed Scopus (3946) Google Scholar]. It has long been known that loss of one subunit can induce the degradation of its partners within the complex [20.Warner J.R. In the absence of ribosomal RNA synthesis, the ribosomal proteins of HeLa cells are synthesized normally and degraded rapidly.J. Mol. Biol. 1977; 115: 315-333Crossref PubMed Scopus (105) Google Scholar], and that non-stoichiometric subunit synthesis can generate stoichiometric complexes [21.Blikstad I. et al.Synthesis and assembly of spectrin during avian erythropoiesis: stoichiometric assembly but unequal synthesis of alpha and beta spectrin.Cell. 1983; 32: 1081-1091Abstract Full Text PDF PubMed Scopus (61) Google Scholar]. An attractive explanation for such behavior is that the stability of proteins is linked to their assembly into complexes. This long-standing hypothesis gained weight after proteomic experiments showed that subunits of protein complexes follow different degradation kinetics in vivo than monomeric proteins [15.McShane E. et al.Kinetic analysis of protein stability reveals age-dependent degradation.Cell. 2016; 167: 803-815Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar]. Supporting this hypothesis, most ubiquitinated proteins are relatively young [24.Kim W. et al.Systematic and quantitative assessment of the ubiquitin-modified proteome.Mol. Cell. 2011; 44: 325-340Abstract Full Text Full Text PDF PubMed Scopus (1157) Google Scholar], and up to 30% of the nascent proteome is degraded shortly after synthesis [22.Schubert U. et al.Rapid degradation of a large fraction of newly synthesized proteins by proteasomes.Nature. 2000; 404: 770-774Crossref PubMed Scopus (1) Google Scholar], although the extent of this degradation remains controversial [15.McShane E. et al.Kinetic analysis of protein stability reveals age-dependent degradation.Cell. 2016; 167: 803-815Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar,23.Vabulas R.M. Hartl F.U. Protein synthesis upon acute nutrient restriction relies on proteasome function.Science. 2005; 310: 1960-1963Crossref PubMed Scopus (254) Google Scholar]. The UPS is the major route for selective protein degradation in eukaryotic cells. Following a three-enzyme (E1–E2–E3) cascade, the 76 amino acid protein ubiquitin is covalently linked to a target protein. A complex code of ubiquitination signals determines the fate of the target protein [25.Komander D. Rape M. The ubiquitin code.Annu. Rev. Biochem. 2012; 81: 203-229Crossref PubMed Scopus (2135) Google Scholar]. Ubiquitination events with lysine 48-containing linkages serve as the main signals for degradation by the 26S proteasome. Lysine 63 linkages, for example, have been associated with NF-κB signaling, DNA repair, and autophagy, a process that degrades misfolded, large, or aggregation-prone cellular components that cannot be removed by the 26S proteasome [25.Komander D. Rape M. The ubiquitin code.Annu. Rev. Biochem. 2012; 81: 203-229Crossref PubMed Scopus (2135) Google Scholar,26.Zaffagnini G. Martens S. Mechanisms of selective autophagy.J. Mol. Biol. 2016; 428: 1714-1724Crossref PubMed Scopus (340) Google Scholar]. The specificity of the UPS is conferred by E3 ubiquitin ligases, which directly engage their substrates through epitopes in the target protein termed degrons [27.Zheng N. Shabek N. Ubiquitin ligases: structure, function, and regulation.Annu. Rev. Biochem. 2017; 86: 129-157Crossref PubMed Scopus (570) Google Scholar]. Although >600 E3 ligases have been identified in human cells [28.Li W. et al.Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.PLoS One. 2008; 3e1487Google Scholar], only a small fraction have known substrate pairings, and most proteins known to undergo ubiquitination, in turn, have not been mapped to a corresponding E3 ligase [29.Meszaros B. et al.Degrons in cancer.Sci. Signal. 2017; 10: eaak9982Crossref PubMed Scopus (60) Google Scholar]. The role of the UPS in the quality control of monomeric proteins is well established [30.Bross P. et al.Protein misfolding and degradation in genetic diseases.Hum. Mutat. 1999; 14: 186-198Crossref PubMed Scopus (191) Google Scholar,31.Lin H.C. et al.CRL2 aids elimination of truncated selenoproteins produced by failed UGA/Sec decoding.Science. 2015; 349: 91-95Crossref PubMed Scopus (42) Google Scholar], and defects in this pathway are associated with cytotoxicity [4.Hipp M.S. et al.Proteostasis impairment in protein-misfolding and -aggregation diseases.Trends Cell Biol. 2014; 24: 506-514Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar]. The UPS has recently been shown to distinguish between and differentially target the monomeric and assembled forms of some substrates, and it has been proposed that such differential targeting plays an important role in correct protein complex assembly. We term this functionality 'assembly quality control' (AQC). AQC E3 ubiquitin ligases target unassembled or incorrectly assembled subunits of protein complexes for degradation to safeguard proteostasis (Figure 1), as exemplified by the following examples.COG complex regulation by Not4The conserved oligomeric Golgi (COG) complex is a ~500 kDa tethering complex that coordinates retrograde vesicle trafficking within the Golgi [32.Ungar D. et al.Subunit architecture of the conserved oligomeric Golgi complex.J. Biol. Chem. 2005; 280: 32729-32735Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar,33.Oka T. et al.Genetic analysis of the subunit organization and function of the conserved oligomeric golgi (COG) complex: studies of COG5- and COG7-deficient mammalian cells.J. Biol. Chem. 2005; 280: 32736-32745Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. Defects in the COG complex affect the cellular glycosylation balance, and mutations in COG subunits result in congenital glycosylation disorders [34.Li G. et al.Compound heterozygous variants of the COG6 gene in a Chinese patient with deficiency of subunit 6 of the conserved oligomeric Golgi complex (COG6-CDG).Eur. J. Med. Genet. 2019; 62: 44-46Crossref Scopus (11) Google Scholar, 35.Yin S. et al.Novel compound heterozygous COG5 mutations in a Chinese male patient with severe clinical symptoms and type IIi congenital disorder of glycosylation: A case report.Exp. Ther. Med. 2019; 18: 2695-2700Google Scholar, 36.Zeevaert R. et al.Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1.Hum. Mol. Genet. 2009; 18: 517-524Crossref PubMed Scopus (41) Google Scholar, 37.Wu X. et al.Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder.Nat. Med. 2004; 10: 518-523Crossref PubMed Scopus (259) Google Scholar]. COG is composed of eight subunits, COG1–8, which are arranged into a bilobed structure in which the two lobes are composed of subunits COG2/3/4 and COG5/6/7, respectively [32.Ungar D. et al.Subunit architecture of the conserved oligomeric Golgi complex.J. Biol. Chem. 2005; 280: 32729-32735Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar,33.Oka T. et al.Genetic analysis of the subunit organization and function of the conserved oligomeric golgi (COG) complex: studies of COG5- and COG7-deficient mammalian cells.J. Biol. Chem. 2005; 280: 32736-32745Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. The two lobes are bridged together by subunits COG1 and COG8 which interact through their N termini [38.Foulquier F. et al.A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1–Cog8 interaction in COG complex formation.Hum. Mol. Genet. 2007; 16: 717-730Crossref PubMed Scopus (107) Google Scholar]. The N terminus of COG1 is acetylated, and the modification directly mediates the interaction with COG8 in the fully assembled complex. This in turn sequesters the COG1 N terminus from the solvent.Around 60% of yeast proteins and 90% of human proteins are N-terminally acetylated [39.Arnesen T. et al.Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans.Proc. Natl. Acad. Sci. U. S. A. 2009; 106: 8157-8162Crossref PubMed Scopus (373) Google Scholar]. N-terminal acetylation (Ac) serves as a recognition signal for a family of E3 ligases named N-recognins which mediate the degradation of N-acetylated substrates through the Ac/N-end pathway [40.Hwang C.S. et al.N-terminal acetylation of cellular proteins creates specific degradation signals.Science. 2010; 327: 973-977Crossref PubMed Scopus (446) Google Scholar]. Yeast Cog1 is N-terminally acetylated in vivo, and the resulting Ac/N-end degron is recognized by the N-recognin Not4 [41.Shemorry A. et al.Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway.Mol. Cell. 2013; 50: 540-551Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar]. This occurs in the monomeric, orphaned form of Cog1, where its exposed acetylated N terminus serves as the degradation signal for the Ac/N-end pathway. In the COG complex, however, the N-terminal acetylation mark in Cog1 is not accessible. Through cycloheximide-chase experiments, it was shown that the half-life of Cog1 depends on the assembly state of the COG complex [41.Shemorry A. et al.Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway.Mol. Cell. 2013; 50: 540-551Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar]. In the absence of stoichiometric amounts of Cog8, as mimicked by Cog1 overexpression, Cog1 is quickly polyubiquitinated by Not4 and subsequently degraded [41.Shemorry A. et al.Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway.Mol. Cell. 2013; 50: 540-551Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar]. In this manner, an E3 ligase is able to read out the assembly state of a protein complex by targeting the free, accessible form of a protein over its complexed, inaccessible counterpart.The same study found analogous regulatory principles for the APC/C complex and its Hcn1 subunit [41.Shemorry A. et al.Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway.Mol. Cell. 2013; 50: 540-551Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar]. Hcn1 is similarly N-terminally acetylated, and its Ac/N-end degron is nested inside a deep chamber formed by the APC/C subunit Cut9 [42.Zhang Z. et al.The APC/C subunit Cdc16/Cut9 is a contiguous tetratricopeptide repeat superhelix with a homo-dimer interface similar to Cdc27.EMBO J. 2010; 29: 3733-3744Crossref PubMed Scopus (61) Google Scholar]. The monomeric, unassembled Hcn1 is quickly ubiquitinated by the Not4 E3 ligase, whereas Hnc1 in the assembled APC/C is spared [41.Shemorry A. et al.Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway.Mol. Cell. 2013; 50: 540-551Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar]. These examples suggest a mechanism whereby stoichiometric complex assembly is controlled by ubiquitin ligases that preferentially target orphan subunits, and this degron-hiding mechanism has been termed 'subunit decoy' [41.Shemorry A. et al.Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway.Mol. Cell. 2013; 50: 540-551Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar].BTB (broad complex, Tramtrack, and Bric-à-brac) dimerization regulation by FBXL17BTB domains are found in >200 human proteins, most of which assemble into CUL3 E3 ubiquitin ligases, transcription factors, and membrane channels to regulate crucial cellular processes such as cell division and differentiation [43.Geyer R. et al.BTB/POZ domain proteins are putative substrate adaptors for cullin 3 ubiquitin ligases.Mol. Cell. 2003; 12: 783-790Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 44.Chevrier S. Corcoran L.M. BTB-ZF transcription factors, a growing family of regulators of early and late B-cell development.Immunol. Cell Biol. 2014; 92: 481-488Crossref PubMed Scopus (26) Google Scholar, 45.Stogios P.J. et al.Sequence and structural analysis of BTB domain proteins.Genome Biol. 2005; 6: R82Crossref PubMed Google Scholar]. To ensure correct signaling output of CUL3 E3 ubiquitin ligases, most BTB proteins must homodimerize. BTB homodimerization is mediated through contacts between each BTB core, and is followed by a strand swap between monomers that connects the dimers through antiparallel β-sheets. Two consecutive studies demonstrated that productive BTB homodimerization is ensured via FBXL17-dependent degradation of misassembled BTB pairs, thereby providing the first molecular mechanism of dimerization quality control [16.Mena E.L. et al.Dimerization quality control ensures neuronal development and survival.Science. 2018; 362: eaap8236Crossref PubMed Scopus (37) Google Scholar,46.Mena E.L. et al.Structural basis for dimerization quality control.Nature. 2020; 586: 452-456Crossref PubMed Scopus (15) Google Scholar].FBXL17 is the substrate-binding module of a CUL1 E3 ubiquitin ligase [27.Zheng N. Shabek N. Ubiquitin ligases: structure, function, and regulation.Annu. Rev. Biochem. 2017; 86: 129-157Crossref PubMed Scopus (570) Google Scholar]. Its F-box domain mediates the interaction with Skp1 that is necessary for its assembly into an E3 ligase, while two motifs in its C-terminal region mediate substrate binding: a solenoid formed by 12 leucine-rich repeats (LRRs) and a C-terminal helix (CTH), which together bind a single BTB domain. In its substrate-bound form, the FBXL17 LRR solenoid closely wraps around the bound BTB domain in a manner that is incompatible with CUL3 binding, while the CTH extends beyond the solenoid to encircle the BTB substrate and block its homodimerization interface [46.Mena E.L. et al.Structural basis for dimerization quality control.Nature. 2020; 586: 452-456Crossref PubMed Scopus (15) Google Scholar]. BTB engagement with FBXL17 is thus mutually exclusive with dimeric BTB assembly into aberrant CUL3 E3 ubiquitin ligase complexes (Figure 2).Figure 2The CUL1FBXL17 E3 ubiquitin ligase ensures correct BTB domain dimerization.Show full captionMisassembled BTB dimers are quickly detected by the CUL1FBXL17 E3 ligase, which polyubiquitinates them for proteasomal degradation [16.Mena E.L. et al.Dimerization quality control ensures neuronal development and survival.Science. 2018; 362: eaap8236Crossref PubMed Scopus (37) Google Scholar]. FBXL17 assembles with the N terminus of CUL1 through adaptor SKP1. At the CUL1 C terminus, RBX1 recruits E2 enzymes to allow substrate ubiquitination. In its substrate-bound form, FBXL17 blocks the interfaces used by BTB proteins for homodimerization and assembly with CUL3 (shown clashing with the FBXL17 LRRs) [46.Mena E.L. et al.Structural basis for dimerization quality control.Nature. 2020; 586: 452-456Crossref PubMed Scopus (15) Google Scholar]. Abbreviations: BTB, broad complex, Tramtrack, and Bric-à-brac; LRR, leucine-rich repeat; Ub, ubiquitin.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Dimerization quality control by FBXL17 significantly differs from the substrate decoy mechanism. Instead of detecting a degron that is hidden in a correctly assembled homodimer, FBXL17 detects an aberrant, metastable dimer interface [16.Mena E.L. et al.Dimerization quality control ensures neuronal development and survival.Science. 2018; 362: eaap8236Crossref PubMed Scopus (37) Google Scholar]. BTB binding to FBXL17 only occurs if the intermolecular β-sheet between monomers is disrupted, and it is the intrinsic instability of the BTB dimer that gates substrate recognition [46.Mena E.L. et al.Structural basis for dimerization quality control.Nature. 2020; 586: 452-456Crossref PubMed Scopus (15) Google Scholar]. In this manner, FBXL17 recognizes the shape of the BTB domain through its LRRs while simultaneously probing the stability of the BTB dimer interface with its CTH. Two physiologically relevant species present such metastable interfaces: inactive heterodimers and mutated homodimers. BTB domains dimerize cotranslationally [12.Bertolini M. et al.Interactions between nascent proteins translated by adjacent ribosomes drive homomer assembly.Science. 2021; 371: 57-64Crossref PubMed Scopus (25) Google Scholar], and aberrant BTB heterodimers arising from stochastic errors in translation are readily detected by FBXL17 [46.Mena E.L. et al.Structural basis for dimerization quality control.Nature. 2020; 586: 452-456Crossref PubMed Scopus (15) Google Scholar]. A small subset of BTB proteins functionally heterodimerize, and these heterodimers appear to evade ubiquitination by FBXL17 [16.Mena E.L. et al.Dimerization quality control ensures neuronal development and survival.Science. 2018; 362: eaap8236Crossref PubMed Scopus (37) Google Scholar].A model was suggested whereby aberrant BTB dimers are detected and ubiquitinated by FBXL17 in a manner reminiscent of an exchange factor [47.Pierce N.W. et al.Cand1 promotes assembly of new SCF complexes through dynamic exchange of F box proteins.Cell. 2013; 153: 206-215Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar]. As such, FBXL17 facilitates the formation of more thermodynamically stable BTB complexes by dissolving and ultimately inducing the degradation of incorrect BTB dimers. A single ligase is thereby capable of proofreading the assembly of a myriad of protein complexes. This elegant dimer quality control mechanism is likely the founding example of AQC systems for modular domains.Hemoglobin quality control by UBE2OErythrocytes transport oxygen transport across human tissues. In healthy adults, 2 million erythrocytes are produced every second in a process termed erythropoiesis [48.Moras M. et al.From erythroblasts to mature red blood cells: organelle clearance in mammals.Front. Physiol. 2017; 8: 1076Crossref PubMed Scopus (133) Google Scholar]. During erythropoiesis, erythrocyte precursors lose most organelles, including mitochondria, ribosomes, and even their nucleus, to become highly specialized in oxygen transport [48.Moras M. et al.From erythroblasts to mature red blood cells: organelle clearance in mammals.Front. Physiol. 2017; 8: 1076Crossref PubMed Scopus (133) Google Scholar]. This crucial function is carried out by the tetrameric protein complex hemoglobin, which is present at ~100 million copies per erythrocyte and constitutes ~98% of the soluble proteome of erythrocytes [49.Bryk A.H. Wisniewski J.R. Quantitative analysis of human red blood cell proteome.J. Proteome Res. 2017; 16: 2752-2761Crossref PubMed Scopus (130) Google Scholar,50.Roux-Dalvai F. et al.Extensive analysis of the cytoplasmic proteome of human erythrocytes using the peptide ligand library technology and advanced mass spectrometry.Mol. Cell. Proteomics. 2008; 7: 2254-2269Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar]. Hemoglobin is composed of two α and two β globin subunits, each of which uses a heme cofactor to bind and transport oxygen. Assembly of hemoglobin occurs in a sequential manner. After synthesis, α-globin is sequestered by the chaperone alpha-hemoglobin-stabilizing protein (AHSP), which binds to and protects a basic and hydrophobic (BH) patch occupied by β-globin in the assembled complex [51.Kihm A.J. et al.An abundant erythroid protein that stabilizes free alpha-haemoglobin.Nature. 2002; 417: 758-763Crossref PubMed Scopus (237) Google Scholar]. AHSP is eventually displaced by β-globin to form an α–β dimer, which then binds to another α–β dimer to form a mature hemoglobin complex. Single α and β subunits have suboptimal oxygen-binding dynamics, and positive cooperativity between the correctly assembled hemoglobin complex is necessary for efficient oxygen transport. Whereas assembled hemoglobin has an exceptionally long half-life, orphaned α-globin precipitates, distorting erythrocyte morphology and triggering their removal by the spleen. In human thalassemia, exaggerated globin precipitation causes anemia [52.Goldberg A.L. 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• W4220997051 created "2022-04-03" @default.
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• W4220997051 date "2022-08-01" @default.
• W4220997051 modified "2023-10-18" @default.
• W4220997051 title "Quality control of protein complex assembly by the ubiquitin–proteasome system" @default.
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• W4220997051 doi "https://doi.org/10.1016/j.tcb.2022.02.005" @default.
• W4220997051 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35300891" @default.
• W4220997051 hasPublicationYear "2022" @default.

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