The molecular mechanism of cotranslational membrane protein recognition and targeting by SecA

Wang, Shuai; Jomaa, Ahmad; Jaskółowski, Mateusz; Yang, Chien-I; Ban, Nenad; Shan, Shu‐ou

doi:10.1038/s41594-019-0297-8

Cited by 29 publications

(34 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A co-translational targeting by SecA has been observed for the inner membrane protein RodZ, which contains a large cytosolic domain preceding its single transmembrane domain ( Rawat et al, 2015 ; Wang et al, 2017 ), and for the periplasmic maltose binding protein MBP ( Huber et al, 2017 ). This is in line with the ability of SecA to interact with translating and non-translating ribosomes ( Eisner et al, 2003 ; Karamyshev and Johnson, 2005 ; Huber et al, 2011 ; Knupffer et al, 2019 ; Origi et al, 2019 ; Wang S. et al, 2019 ). On the other hand, a post-translational interaction of SRP has been shown for the small bacterial membrane proteins YohP and YkgR ( Steinberg et al, 2020 ) and for the tail-anchored proteins DjlC, Flk, and SciP ( Pross et al, 2016 ; Peschke et al, 2018 ).…”

Section: Targeting the Secyeg Transloconsupporting

confidence: 76%

The Dynamic SecYEG Translocon

Oswald

Njenga

Natriashvili

et al. 2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

The spatial and temporal coordination of protein transport is an essential cornerstone of the bacterial adaptation to different environmental conditions. By adjusting the protein composition of extra-cytosolic compartments, like the inner and outer membranes or the periplasmic space, protein transport mechanisms help shaping protein homeostasis in response to various metabolic cues. The universally conserved SecYEG translocon acts at the center of bacterial protein transport and mediates the translocation of newly synthesized proteins into and across the cytoplasmic membrane. The ability of the SecYEG translocon to transport an enormous variety of different substrates is in part determined by its ability to interact with multiple targeting factors, chaperones and accessory proteins. These interactions are crucial for the assisted passage of newly synthesized proteins from the cytosol into the different bacterial compartments. In this review, we summarize the current knowledge about SecYEG-mediated protein transport, primarily in the model organism Escherichia coli, and describe the dynamic interaction of the SecYEG translocon with its multiple partner proteins. We furthermore highlight how protein transport is regulated and explore recent developments in using the SecYEG translocon as an antimicrobial target.

show abstract

Section: Targeting the Secyeg Transloconsupporting

confidence: 76%

The Dynamic SecYEG Translocon

Oswald

Njenga

Natriashvili

et al. 2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…It is intimately associated with the SecYEG translocon, and it uses ATP to drive post-translational polypeptides through the pore into the periplasm [reviewed by (26)]. Recent work has shown that SecA mimics the properties of the SRP (90,91). Thus, the use of superfamily 2 proteins for polypeptide translocation across membranes may be conserved throughout evolution.…”

Section: Discussionmentioning

confidence: 99%

The DEAD-box RNA helicase Ded1 from yeast is associated with the signal recognition particle (SRP), and its enzymatic activity is regulated by SRP21

Tanner

Yeter-Alat

Belgareh‐Touzé

et al. 2020

Preprint

View full text Add to dashboard Cite

The DEAD-box RNA helicase Ded1 is an essential yeast protein involved in translation initiation. It belongs to the DDX3 subfamily of proteins implicated in developmental and cell-cycle regulation. In vitro, the purified Ded1 protein is an ATP-dependent RNA binding protein and an RNA-dependent ATPase, but it lacks RNA substrate specificity and enzymatic regulation. Here we demonstrate by yeast genetics, in situ localization and in vitro biochemical approaches that Ded1 is associated with, and regulated by, the signal recognition particle (SRP), which is a universally conserved ribonucleoprotein complex required for the co-translational translocation of polypeptides into the endoplasmic reticulum lumen and membrane. Ded1 is physically associated with SRP components in vivo and in vitro. Ded1 is genetically linked with SRP proteins. Finally, the enzymatic activity of Ded1 is inhibited by SRP21 with SCR1 RNA. We propose a model where Ded1 actively participates in the translocation of proteins during translation. Our results open a new comprehension of the cellular role of Ded1 during translation.

show abstract

“…Molecular docking is one of the most benefit and theoretical tools to predict the structure of complexes formed by small‐molecule ligand and protein (Du et al, 2016; Kosol et al, 2019; Lyu et al, 2019; S. Wang et al, 2019). We then use molecular simulation to further reveal the detailed interaction model between shikonin and IMPDH2.…”

Section: Resultsmentioning

confidence: 99%

Shikonin is a novel and selective IMPDH2 inhibitor that target triple‐negative breast cancer

Wang

Chen

et al. 2020

Phytotherapy Research

View full text Add to dashboard Cite

Triple‐negative breast cancer (TNBC) is heterogeneous disease with a poor prognosis. It is therefore important to explore novel therapeutic agents to improve the clinical efficacy for TNBC. The inosine 5′‐monophosphate dehydrogenase 2 (IMPDH2) is a rate‐limiting enzyme in the de novo synthesis of guanine nucleotides. It is always overexpressed in many types of tumors, including TNBC and regarded as a potential target for cancer therapy. Through screening a library of natural products, we identified shikonin, a natural bioactive component of Lithospermum erythrorhizon, is a novel and selective IMPDH2 inhibitor. Enzymatic analysis using Lineweaver–Burk plot indicates that shikonin is a competitive inhibitor of IMPDH2. The interaction between shikonin and IMDPH2 was further investigated by thermal shift assay, fluorescence quenching, and molecular docking simulation. Shikonin treatment effectively inhibits the growth of human TNBC cell line MDA‐MB‐231, and murine TNBC cell line, 4T1 in a dose‐dependent manner, which is impaired by exogenous supplementation of guanosine, a salvage pathway of purine nucleotides. Most importantly, IMPDH2 knockdown significantly reduced cell proliferation and conferred resistance to shikonin in TNBC. Collectively, our findings showed the natural product shikonin as a selective inhibitor of IMPDH2 with anti‐TNBC activity, impelling its further study in clinical trials.

show abstract

The molecular mechanism of cotranslational membrane protein recognition and targeting by SecA

Cited by 29 publications

References 65 publications

The Dynamic SecYEG Translocon

The Dynamic SecYEG Translocon

The DEAD-box RNA helicase Ded1 from yeast is associated with the signal recognition particle (SRP), and its enzymatic activity is regulated by SRP21

Shikonin is a novel and selective IMPDH2 inhibitor that target triple‐negative breast cancer

Contact Info

Product

Resources

About