Structures of human SRP72 complexes provide insights into SRP RNA remodeling and ribosome interaction

Becker, Matthias M.M.; Lapouge, Karine; Segnitz, Bernd; Wild, Klemens; Sinning, Irmgard

doi:10.1093/nar/gkw1124

Cited by 23 publications

(40 citation statements)

References 63 publications

(102 reference statements)

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“…Herein, we solved the first SRP68/72 complex structure at atomic resolution (1.7 Å). In the final phase of manuscript submission, a similar structure of a SRP68/72 complex was reported ( Becker et al, 2017 ). In our study, we identified the minimal domains of both SRP68 and SRP72 that are necessary and sufficient for their interaction, and found a C-terminal capping helix in SRP72 that is required for tight binding.…”

Section: Discussionmentioning

confidence: 69%

Human apo-SRP72 and SRP68/72 complex structures reveal the molecular basis of protein translocation

Gao

Zhang

Lang

et al. 2017

Journal of Molecular Cell Biology

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The co-translational targeting or insertion of secretory and membrane proteins into the endoplasmic reticulum (ER) is a key biological process mediated by the signal recognition particle (SRP). In eukaryotes, the SRP68–SRP72 (SRP68/72) heterodimer plays an essential role in protein translocation. However, structural information on the two largest SRP proteins, SRP68 and SRP72, is limited, especially regarding their interaction. Herein, we report the first crystal structures of human apo-SRP72 and the SRP68/72 complex at 2.91Å and 1.7Å resolution, respectively. The SRP68-binding domain of SRP72 contains four atypical tetratricopeptide repeats (TPR) and a flexible C-terminal cap. Apo-SRP72 exists mainly as dimers in solution. To bind to SRP68, the SRP72 homodimer disassociates, and the indispensable C-terminal cap undergoes a pronounced conformational change to assist formation of the SRP68/72 heterodimer. A 23-residue polypeptide of SRP68 is sufficient for tight binding to SRP72 through its unusually hydrophobic and extended surface. Structural, biophysical, and mutagenesis analyses revealed that cancer-associated mutations disrupt the SRP68–SRP72 interaction and their co-localization with ER in mammalian cells. The results highlight the essential role of the SRP68–SRP72 interaction in SRP-mediated protein translocation and provide a structural basis for disease diagnosis, pathophysiology, and drug design.

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Section: Discussionmentioning

confidence: 69%

Human apo-SRP72 and SRP68/72 complex structures reveal the molecular basis of protein translocation

Gao

Zhang

Lang

et al. 2017

Journal of Molecular Cell Biology

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“…Similarly, NUP98 can also be utilized for viral entry into the nucleus. Additional three CSPs in this category, RPL36 and RPS20 40, 60 as well as SRP72 61 , could be employed for viral transcription and protein synthesis (Fig. 3e).…”

Section: Discussionmentioning

confidence: 99%

Integrative Network Biology Framework Elucidates Molecular Mechanisms of SARS-CoV-2 Pathogenesis

Kumar

Mishra

Mehmood

et al. 2020

Preprint

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COVID-19 (Coronavirus disease 2019) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the pathophysiology of this deadly virus is complex and largely unknown, we employ a network biology-fueled approach and integrated multiomics data pertaining to lung epithelial cells-specific coexpression network and human interactome to generate Calu-3-specific human-SARS-CoV-2 Interactome (CSI). Topological clustering and pathway enrichment analysis show that SARS-CoV-2 target central nodes of host-viral network that participate in core functional pathways. Network centrality analyses discover 28 high-value SARS-CoV-2 targets, which are possibly involved in viral entry, proliferation and survival to establish infection and facilitate disease progression. Our probabilistic modeling framework elucidates critical regulatory circuitry and molecular events pertinent to COVID-19, particularly the host modifying responses and cytokine storm. Overall, our network centric analyses reveal novel molecular components, uncover structural and functional modules, and provide molecular insights into SARS-CoV-2 pathogenicity.

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“…Bacterial complexes of the closed state depicted an NG heterodimer detached from the SRP RNA tetraloop in which the distal region of the SRP RNA could not be fully visualized due to flexibility918. Previous cryo-EM studies on the eukaryotic SRP–SR complex revealed an additional density at the SRP distal region19 that was recently interpreted by docking a crystal structure of the eukaryotic NG heterodimer into this density202122.…”

mentioning

confidence: 99%

Structure of the quaternary complex between SRP, SR, and translocon bound to the translating ribosome

Jomaa

Boehringer

et al. 2017

Nat Commun

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During co-translational protein targeting, the signal recognition particle (SRP) binds to the translating ribosome displaying the signal sequence to deliver it to the SRP receptor (SR) on the membrane, where the signal peptide is transferred to the translocon. Using electron cryo-microscopy, we have determined the structure of a quaternary complex of the translating Escherichia coli ribosome, the SRP–SR in the ‘activated' state and the translocon. Our structure, supported by biochemical experiments, reveals that the SRP RNA adopts a kinked and untwisted conformation to allow repositioning of the ‘activated' SRP–SR complex on the ribosome. In addition, we observe the translocon positioned through interactions with the SR in the vicinity of the ribosome exit tunnel where the signal sequence is extending beyond its hydrophobic binding groove of the SRP M domain towards the translocon. Our study provides new insights into the mechanism of signal sequence transfer from the SRP to the translocon.

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Structures of human SRP72 complexes provide insights into SRP RNA remodeling and ribosome interaction

Cited by 23 publications

References 63 publications

Human apo-SRP72 and SRP68/72 complex structures reveal the molecular basis of protein translocation

Human apo-SRP72 and SRP68/72 complex structures reveal the molecular basis of protein translocation

Integrative Network Biology Framework Elucidates Molecular Mechanisms of SARS-CoV-2 Pathogenesis

Structure of the quaternary complex between SRP, SR, and translocon bound to the translating ribosome

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