Compartmentalization-aided interaction screening reveals extensive high-order complexes within the SARS-CoV-2 proteome

Xu, Weifan; Pei, Gaofeng; Liu, Hongrui; Ju, Xiaohui; Wang, Jing; Ding, Qiang; Li, Pilong

doi:10.1016/j.celrep.2021.109482

Cited by 19 publications

(11 citation statements)

References 110 publications

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“…While the molecular basis for oligomerization is still not fully understood 19 , it has been proposed that the Nsp15 hexamer functions as the central scaffold for the RTC to coordinate the RTC's numerous enzymatic activities by serving as a platform for binding dsRNA generated during replication 5 . This model is further supported by work establishing that Nsp15 co-localizes with members of the RTC 21,22 .…”

Section: Main Textmentioning

confidence: 72%

Flipped Over U: Structural Basis for dsRNA Cleavage by the SARS-CoV-2 Endoribonuclease

Frazier

Wilson

Krahn

et al. 2022

Preprint

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Coronaviruses generate double-stranded (ds) RNA intermediates during viral replication that can activate host immune sensors. To evade activation of the host pattern recognition receptor MDA5, coronaviruses employ Nsp15, which is uridine-specific endoribonuclease. Nsp15 is proposed to associate with the coronavirus replication-transcription complex within double-membrane vesicles to cleave these dsRNA intermediates. How Nsp15 recognizes and processes dsRNA is poorly understood because previous structural studies of Nsp15 have been limited to small single-stranded (ss) RNA substrates. Here we present cryo-EM structures of SARS-CoV-2 Nsp15 bound to a 52nt dsRNA. We observed that the Nsp15 hexamer forms a platform for engaging dsRNA across multiple protomers. The structures, along with site-directed mutagenesis and RNA cleavage assays revealed critical insight into dsRNA recognition and processing. To process dsRNA Nsp15 utilizes a base-flipping mechanism to properly orient the uridine within the active site for cleavage. Our findings show that Nsp15 is a distinctive endoribonuclease that can cleave both ss- and dsRNA effectively.

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Section: Main Textmentioning

confidence: 72%

Flipped Over U: Structural Basis for dsRNA Cleavage by the SARS-CoV-2 Endoribonuclease

Frazier

Wilson

Krahn

et al. 2022

Preprint

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“…Although our study has uncovered the existence of commonalities and differences in the SARS-CoV-2 structural protein functionality, potential limitations exist that warrant discussion. It is important to note that SARS-CoV-2 structural and non-structural protein interactions are absent in our study (Boson et al, 2021;Xu et al, 2021). We are aware that using our multi-omic approach, the molecular dimension generated by posttranslational modifications (i.e phosphorylation) not only in host proteins but also in the SARS-CoV-2 structural proteins (Stukalov et al, 2021) has not been considered in this study, hampering the characterization of potential substrates modulated by the virus-hijacked kinase activation profiles.…”

Section: Proteotranscriptomic Data Integration By Machine Learning Un...mentioning

confidence: 84%

Metabolic dyshomeostasis induced by SARS-CoV-2 structural proteins reveals immunological insights into viral olfactory interactions

Lachén-Montes

Mendizuri

Ausín

et al. 2022

Preprint

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One of the most common symptoms in COVID-19 is a sudden loss of smell. SARS-CoV-2 has been detected in the olfactory bulb (OB) from animal models and sporadically in COVID-19 patients. To decipher the specific role over the SARS-CoV-2 proteome at olfactory level, we characterized the in-depth molecular imbalance induced by the expression of GFP-tagged SARS-CoV-2 structural proteins (M, N, E, S) on mouse OB cells. Transcriptomic and proteomic trajectories uncovered a widespread metabolic remodeling commonly converging in extracellular matrix organization, lipid metabolism and signaling by receptor tyrosine kinases. The molecular singularities and specific interactome expression modules were also characterized for each viral structural factor. The intracellular molecular imbalance induced by each SARS-CoV-2 structural protein was accompanied by differential activation dynamics in survival and immunological routes in parallel with a differentiated secretion profile of chemokines in OB cells. Machine learning through a proteotranscriptomic data integration uncovered TGF-beta signaling as a confluent activation node by the SARS-CoV-2 structural proteome. Taken together, these data provide important avenues for understanding the multifunctional immunomodulatory properties of SARS-CoV-2 M, N, S and E proteins beyond their intrinsic role in virion formation, deciphering mechanistic clues to the olfactory inflammation observed in COVID-19 patients.

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“…Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as the causative agent of coronavirus disease-2019 (COVID-19), has led to more than 630 million confirmed cases and 6.6 million deaths globally 37 , and seriously affected people’s normal life 38 . The SARS-CoV-2 proteins potentially interact with multiple human proteins after the virus infects human cells 39 .…”

Section: Resultsmentioning

confidence: 99%

HPC-Atlas: Computationally Constructing A Comprehensive Atlas of Human Protein Complexes

Pan

Ruiyi

et al. 2023

Preprint

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A fundamental principle of biology is that proteins tend to form complexes to play significant roles in the core functions of cells. For a complete understanding of human cellular functions, we require a comprehensive atlas of human protein complexes. Unfortunately, we still lack such a comprehensive atlas of experimentally validated protein complexes, which prevents us from gaining a complete understanding of the compositions and functions of human protein complexes and biological mechanisms. To fill this gap, we built HPC-Atlas, as far as we know, the most accurate and comprehensive atlas of human protein complexes available to date. We integrated two latest protein interaction networks, and developed a novel computational method to identify nearly 9000 protein complexes, including many previously uncharacterized complexes. Compared with the existing works, our method achieves outstanding performance on both test and independent sets. Furthermore, with HPC-Atlas we also identified 751 SARS-CoV-2 affected human protein complexes, and 456 multifunctional proteins that contain many potential moonlighting proteins. These results suggest that HPC-Atlas can serve as not only a computing framework to effectively integrate new protein data sources for identifying biologically meaningful protein complexes, but also a valuable resource for exploring new biological findings. The HPC-Atlas webserver is freely available at http://www.yulpan.top/HPC-Atlas.

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Compartmentalization-aided interaction screening reveals extensive high-order complexes within the SARS-CoV-2 proteome

Cited by 19 publications

References 110 publications

Flipped Over U: Structural Basis for dsRNA Cleavage by the SARS-CoV-2 Endoribonuclease

Flipped Over U: Structural Basis for dsRNA Cleavage by the SARS-CoV-2 Endoribonuclease

Metabolic dyshomeostasis induced by SARS-CoV-2 structural proteins reveals immunological insights into viral olfactory interactions

HPC-Atlas: Computationally Constructing A Comprehensive Atlas of Human Protein Complexes

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