Keeping the Proportions of Protein Complex Components in Check

Taggart, James; Zauber, Henrik; Selbach, Matthias; Li, Gene-Wei; McShane, Erik

doi:10.1016/j.cels.2020.01.004

Cited by 85 publications

(96 citation statements)

References 62 publications

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“…Highlighted proteins from differential abundance with age analysis.Loss of stoichiometry in protein complexes has been shown to occur with age in a number of organisms(69,70). We asked how the balance of component proteins in key age-related complexes was regulated at both the transcript and protein level.…”

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confidence: 99%

Genome-wide transcript and protein analysis reveals distinct features of aging in the mouse heart

Gyuricza

Chick

Keele

et al. 2020

Preprint

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Understanding the molecular mechanisms underlying age-related changes in the heart is challenging due to the contributions from numerous genetic and environmental factors. Genetically diverse outbred mice provide a model to study the genetic regulation of aging processes in healthy tissues from individuals undergoing natural aging in a controlled environment. We analyzed transcriptome and proteome data from outbred mice at 6, 12 and 18 months of age to reveal a scenario of cardiac hypertrophy, fibrosis, extracellular matrix remodeling, and reemergence of fetal gene expression patterns. We observed widespread changes in protein trafficking and sorting, and post-translational disruption of the stoichiometry of the protein quality control system itself. We identified genome hotspots of age-by-genetic effects that regulate proteins from the proteasome and endoplasmic reticulum stress response, suggesting that genetic variation in these modules may contribute to individual variation in the aging heart.

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confidence: 99%

Genome-wide transcript and protein analysis reveals distinct features of aging in the mouse heart

Gyuricza

Chick

Keele

et al. 2020

Preprint

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“…With all interfaces matched up to a partner, perfect balance also minimizes the formation of mis-interactions that can result from leftover subunits that assemble in nonfunctional complexes due to the sticky hydrophobic surfaces of proteins 18–20 . Experimental evidence supports stoichiometric balance for proteins involved in highly stable complex formation 2,21,22 . We recently extended this idea of stoichiometric balance to larger networks where each protein may have interfaces with multiple competing partners 23 .…”

Section: Introductionmentioning

confidence: 70%

Integrating protein copy numbers with interaction networks to quantify stoichiometry in mammalian endocytosis

Duan

et al. 2020

Preprint

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Proteins that drive processes like clathrin-mediated endocytosis (CME) are expressed at various copy numbers within a cell, from hundreds (e.g. auxilin) to millions (e.g. clathrin). Between cell types with identical genomes, copy numbers further vary significantly both in absolute and relative abundance. These variations contain essential information about each protein's function, but how significant are these variations and how can they be quantified to infer useful functional behavior? Here, we address this by quantifying the stoichiometry of proteins involved in the CME network. We find robust trends across three cell types in proteins that are sub- vs super-stoichiometric in terms of protein function, network topology (e.g. hubs), and abundance. To perform this analysis, we first constructed the interface resolved network of 82 proteins involved in CME in mammals, plus lipid and cargo binding partners, totaling over 600 specific binding interactions. Our model solves for stoichiometric balance by optimizing each copy of a protein interface to match up to its partner interfaces, keeping the optimized copies as close as possible to observed copies. We find highly expressed, structure-forming proteins such as actin and clathrin do tend to be super-stoichiometric, or in excess of their partners, but they are not the most extreme cases. We test sensitivity of network stoichiometry to protein removal and find that hub proteins tend to be less sensitive to removal of any single partner, thus acting as buffers that compensate dosage changes. As expected, tightly coupled protein pairs (e.g. CAPZA2 and CAPZB) are strongly correlated. Unexpectedly, removal of functionally similar cargo adaptor proteins produces widely variable levels of disruption to the network stoichiometry. Our results predict that knockdown of the adaptor protein DAB2 will globally impact the stoichiometry of most other cargo adaptor proteins in Hela cells, with significantly less impact in fibroblast cells. This inexpensive analysis can be applied to any protein network, synthesizing disparate sources of biological data into a relatively simple and intuitive model of binding stoichiometry that can aid in dynamical modeling and experimental design.

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“…We observed enhanced levels of SVR7 protein in not4a relative to WT (Figure S6B), perhaps compensating for loss of PGR3 , and explaining why 50S subunits are not affected. In contrast, defects in Rps8 translation due to loss of PGR3 in not4a likely explains why ribosome depletion is specific to the 30S subunit, since protein complex stoichiometries are highly regulated, with the inability to assemble complete complexes often leading to degradation of orphan subunits (Juszkiewicz and Hegde, 2018; Taggart et al, 2020). In addition, upregulation of PPR proteins SOT1, EMB2654, PPR4 and PPR2 (which all promote chloroplast rRNA maturation), and GUN1 (implicated in the production of chloroplast ribosomal subunits RPS1 and RPL11) present further evidence of compensatory responses to reduced ribosome abundance and protein synthesis within not4a chloroplasts (Figure S6B)(Aryamanesh et al, 2017; Lee et al, 2019; Lu et al, 2011; Tadini et al, 2016; Wu et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

TheArabidopsisNOT4A E3 ligase coordinates PGR3 expression to regulate chloroplast protein translation

Bailey

Ivanauskaite

Grimmer

et al. 2020

Preprint

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31Chloroplast function requires the coordinated action of nuclear-and chloroplast-derived 32 proteins, including several hundred nuclear-encoded pentatricopeptide repeat (PPR) 33 proteins that regulate plastid mRNA metabolism. Despite their large number and importance, 34 regulatory mechanisms controlling PPR expression are poorly understood. Here we show 35 that the Arabidopsis NOT4A ubiquitin-ligase positively regulates PROTON GRADIENT 3 36 (PGR3), a PPR protein required for translating 30S ribosome subunits and several thylakoid-37 localised photosynthetic components within chloroplasts. Loss of NOT4A function leads to a 38 strong depletion of plastid ribosomes, which reduces mRNA translation and negatively 39 impacts photosynthetic capacity, causing pale-yellow and slow-growth phenotypes. 40Quantitative transcriptome and proteome analyses reveal that these defects are due to a 41 lack of PGR3 expression in not4a, and we show that normal plastid function is restored 42 through transgenic PGR3 expression. Our work identifies NOT4A as crucial for ensuring 43 robust photosynthetic function during development and stress-response, through modulating 44 PGR3 levels to coordinate chloroplast protein synthesis.The synthesis of energy from the sun, photosynthesis, supports organic life on earth. Light 68 harvesting in green plants takes place within the specialized chloroplast organelle, believed 69 to have arisen from engulfment of a photosynthetic prokaryote by an ancestral eukaryotic 70 cell (Archibald, 2015). Coevolution and merging of these organisms has resulted in nuclear 71 and chloroplast genomes separated within cellular compartments. In land plants, the 72 chloroplast genome comprises of ~130 genes, yet chloroplasts contain around 3000 different 73 proteins (Zoschke and Bock, 2018). Consequently, chloroplast function requires expression 74 not only of chloroplast encoded proteins, but a multitude of nuclear encoded genes, which 75 are imported into chloroplasts post-translationally. One such group of nuclear derived factors 76 is the pentatricopeptide repeat domain (PPR) containing proteins. The PPR protein family 77 has significantly expanded in plants (~450 in Arabidopsis, vs <10 in humans and yeast; 78 (Schmitz-Linneweber and Small, 2008)), and members are characterized by a 35-amino acid 79 repeat sequence that facilitates RNA binding and enables them to provide critical gene 80 expression control within chloroplasts and mitochondria (Barkan and Small, 2014). Through 81 binding to organellar RNAs, PPR proteins stabilize gene transcripts, facilitate post-82 transcriptional processing and promote translation of the encoded proteins (Barkan and 83 Small, 2014; Manna, 2015). Whilst their function in the regulation of gene expression control 84 within organelles has been described, including many of the RNA species to which they 85 bind, little is known about how their expression is regulated prior to import. 86Precise, selective removal of proteins is essential to cellular development and response. In 87...

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Keeping the Proportions of Protein Complex Components in Check

Cited by 85 publications

References 62 publications

Genome-wide transcript and protein analysis reveals distinct features of aging in the mouse heart

Genome-wide transcript and protein analysis reveals distinct features of aging in the mouse heart

Integrating protein copy numbers with interaction networks to quantify stoichiometry in mammalian endocytosis

TheArabidopsisNOT4A E3 ligase coordinates PGR3 expression to regulate chloroplast protein translation

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