CEDAR, an online resource for the reporting and exploration of complexome profiling data

Strien, Joeri van; Haupt,; Schulte, Mitchell D.; Braun, Hans‐Peter; Cabrero-Orefice,; Choudhary, Jyoti S.; Evers, Felix; Fernández-Vizarra, Erika; Guerrero-Castillo,; Kooij, Taco W. A.; Palenikova,; Pardo,; Ugalde,; Wohlbrand,; Brandt,; Arnold, Matthew D.; Huynen,

doi:10.1101/2020.12.11.421172

Cited by 7 publications

(4 citation statements)

References 60 publications

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“…Across all samples (662 fractions) a total of 1759 unique proteins were identified (Supplementary Data 1). All raw and processed data generated in this study were deposited at the ComplexomE profiling DAta Resource (CEDAR; www3.cmbi.umcn.nl/cedar/browse/experiments/CRX23) 29 .…”

Section: Resultsmentioning

confidence: 99%

Composition and stage dynamics of mitochondrial complexes in Plasmodium falciparum

et al. 2021

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Our current understanding of mitochondrial functioning is largely restricted to traditional model organisms, which only represent a fraction of eukaryotic diversity. The unusual mitochondrion of malaria parasites is a validated drug target but remains poorly understood. Here, we apply complexome profiling to map the inventory of protein complexes across the pathogenic asexual blood stages and the transmissible gametocyte stages of Plasmodium falciparum. We identify remarkably divergent composition and clade-specific additions of all respiratory chain complexes. Furthermore, we show that respiratory chain complex components and linked metabolic pathways are up to 40-fold more prevalent in gametocytes, while glycolytic enzymes are substantially reduced. Underlining this functional switch, we find that cristae are exclusively present in gametocytes. Leveraging these divergent properties and stage dynamics for drug development presents an attractive opportunity to discover novel classes of antimalarials and increase our repertoire of gametocytocidal drugs.

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Section: Resultsmentioning

confidence: 99%

Composition and stage dynamics of mitochondrial complexes in Plasmodium falciparum

et al. 2021

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“…The increasing availability of complexome profiling data from various species in the public CEDAR database has opened the door for large scale and automated analysis of these data (13). However, methods that enable automated large-scale comparative analysis of protein interaction data to exploit this wealth of information were lacking.…”

Section: Discussionmentioning

confidence: 99%

“…Since the initial application of the complexome profiling approach, an increasing number of complexome profiling datasets have been generated from at least 21 different species, covering all kingdoms of life (1), which are available from the CEDAR database of complexome profiles (13). Leveraging these data in comparative analyses in principle has the potential for more sensitive detection of novel interactors and to facilitate analyses of the evolution of protein complexes.…”

Section: Introductionmentioning

confidence: 99%

Comparative Clustering (CompaCt) of eukaryote complexomes identifies novel interactions and sheds light on protein complex evolution

Strien¹,

Evers

Lutikurti

et al. 2023

Preprint

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Complexome profiling allows large-scale, untargeted, and comprehensive characterization of protein complexes in a biological sample using a combined approach of separating intact protein complexes e.g., by native gel electrophoresis, followed by mass spectrometric analysis of the proteins in the resulting fractions. Over the last decade, its application has resulted in a large collection of complexome profiling datasets. While computational methods have been developed for the analysis of individual datasets, methods for large-scale comparative analysis of complexomes from multiple species are lacking. Here, we present Comparative Clustering (CompaCt), that performs fully automated integrative analysis of complexome profiling data from multiple species, enabling systematic characterization and comparison of complexomes. CompaCt implements a novel method for leveraging orthology in comparative analysis to allow systematic identification of conserved as well as taxon-specific elements of the analyzed complexomes. We applied this method to a collection of 53 complexome profiles spanning the major branches of the eukaryotes. We demonstrate the ability of CompaCt to robustly identify the composition of protein complexes, and show that integrated analysis of multiple datasets improves characterization of complexes from specific complexome profiles when compared to separate analysis. We identified novel candidate interactors and complexes in a number of species from previously analyzed datasets, like the emp24, the V-ATPase and mitochondrial ATP synthase complexes. Lastly, we demonstrate the utility of CompaCt for the automated large-scale characterization of the complexome of the mosquito Anopheles stephensi shedding light on the evolution of metazoan protein complexes. CompaCt is available from https://github.com/cmbi/compact-bio.

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“…The relative peptide intensity profile of each protein was normalized to the slice with the highest intensity from the average of duplicate experiments and was visualized in heatmaps using Microsoft Excel and Prism 8 (GraphPad Software, La Jolla California USA). Complexome profiling dataset is publicly available in the CEDAR database [48] (https://www3.cmbi.umcn.nl/cedar/browse),, accession number CRX25 (accessed on December 22 nd 2020).…”

Section: Stable Isotope Labeling Using Amino Acids In Cell Culture (Smentioning

confidence: 99%

Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis

Čunátová

Reguera

Vrbacký

et al. 2021

Cells

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The oxidative phosphorylation (OXPHOS) system localized in the inner mitochondrial membrane secures production of the majority of ATP in mammalian organisms. Individual OXPHOS complexes form supramolecular assemblies termed supercomplexes. The complexes are linked not only by their function but also by interdependency of individual complex biogenesis or maintenance. For instance, cytochrome c oxidase (cIV) or cytochrome bc1 complex (cIII) deficiencies affect the level of fully assembled NADH dehydrogenase (cI) in monomeric as well as supercomplex forms. It was hypothesized that cI is affected at the level of enzyme assembly as well as at the level of cI stability and maintenance. However, the true nature of interdependency between cI and cIV is not fully understood yet. We used a HEK293 cellular model where the COX4 subunit was completely knocked out, serving as an ideal system to study interdependency of cI and cIV, as early phases of cIV assembly process were disrupted. Total absence of cIV was accompanied by profound deficiency of cI, documented by decrease in the levels of cI subunits and significantly reduced amount of assembled cI. Supercomplexes assembled from cI, cIII, and cIV were missing in COX4I1 knock-out (KO) due to loss of cIV and decrease in cI amount. Pulse-chase metabolic labeling of mitochondrial DNA (mtDNA)-encoded proteins uncovered a decrease in the translation of cIV and cI subunits. Moreover, partial impairment of mitochondrial protein synthesis correlated with decreased content of mitochondrial ribosomal proteins. In addition, complexome profiling revealed accumulation of cI assembly intermediates, indicating that cI biogenesis, rather than stability, was affected. We propose that attenuation of mitochondrial protein synthesis caused by cIV deficiency represents one of the mechanisms, which may impair biogenesis of cI.

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CEDAR, an online resource for the reporting and exploration of complexome profiling data

Cited by 7 publications

References 60 publications

Composition and stage dynamics of mitochondrial complexes in Plasmodium falciparum

Composition and stage dynamics of mitochondrial complexes in Plasmodium falciparum

Comparative Clustering (CompaCt) of eukaryote complexomes identifies novel interactions and sheds light on protein complex evolution

Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis

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