scholarly journals Substrate-gated docking of pore subunit Tha4 in the TatC cavity initiates Tat translocase assembly

2014 ◽  
Vol 205 (1) ◽  
pp. 51-65 ◽  
Author(s):  
Cassie Aldridge ◽  
Xianyue Ma ◽  
Fabien Gerard ◽  
Kenneth Cline
Keyword(s):  
Signal Peptide ◽  
Receptor Complex ◽  
Core Component ◽  
The Core ◽  
Contact Sites ◽  
Contact Data ◽  
Folded Proteins ◽  
Twin Arginine Translocase ◽  
Enclosed Chamber

The twin-arginine translocase (Tat) transports folded proteins across tightly sealed membranes. cpTatC is the core component of the thylakoid translocase and coordinates transport through interactions with the substrate signal peptide and other Tat components, notably the Tha4 pore-forming component. Here, Cys–Cys matching mapped Tha4 contact sites on cpTatC and assessed the role of signal peptide binding on Tha4 assembly with the cpTatC–Hcf106 receptor complex. Tha4 made contact with a peripheral cpTatC site in nonstimulated membranes. In the translocase, Tha4 made an additional contact within the cup-shaped cavity of cpTatC that likely seeds Tha4 polymerization to form the pore. Substrate binding triggers assembly of Tha4 onto the interior site. We provide evidence that the substrate signal peptide inserts between cpTatC subunits arranged in a manner that conceivably forms an enclosed chamber. The location of the inserted signal peptide and the Tha4–cpTatC contact data suggest a model for signal peptide–gated Tha4 entry into the chamber to form the translocase.

scholarly journals Mitochondria-driven assembly of a cortical anchor for mitochondria and dynein

2017 ◽  
Vol 216 (10) ◽  
pp. 3061-3071 ◽  
Author(s):  
Lauren M. Kraft ◽  
Laura L. Lackner
Keyword(s):  
Plasma Membrane ◽  
Mitotic Spindle ◽  
Cell Cortex ◽  
Dual Function ◽  
Mitochondrial Inheritance ◽  
Cellular Functions ◽  
Core Component ◽  
Spindle Positioning ◽  
The Core ◽  
Contact Sites

Interorganelle contacts facilitate communication between organelles and impact fundamental cellular functions. In this study, we examine the assembly of the MECA (mitochondria–endoplasmic reticulum [ER]–cortex anchor), which tethers mitochondria to the ER and plasma membrane. We find that the assembly of Num1, the core component of MECA, requires mitochondria. Once assembled, Num1 clusters persistently anchor mitochondria to the cell cortex. Num1 clusters also function to anchor dynein to the plasma membrane, where dynein captures and walks along astral microtubules to help orient the mitotic spindle. We find that dynein is anchored by Num1 clusters that have been assembled by mitochondria. When mitochondrial inheritance is inhibited, Num1 clusters are not assembled in the bud, and defects in dynein-mediated spindle positioning are observed. The mitochondria-dependent assembly of a dual-function cortical anchor provides a mechanism to integrate the positioning and inheritance of the two essential organelles and expands the function of organelle contact sites.

scholarly journals The Vacuole and Mitochondria Patch (vCLAMP) Protein Mcp1 Is Involved in Maintenance of Mitochondrial Function and Mitophagy in Candida albicans

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaolong Mao ◽  
Li Yang ◽  
Yiming Fan ◽  
Jiazhen Wang ◽  
Dongkai Cui ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Carbon Sources ◽  
Cellular Functions ◽  
Core Component ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Mitochondrial Functions ◽  
Abnormal Accumulation ◽  
Membrane Contact

The vacuole and mitochondria patches (vCLAMPs) are novel membrane contact sites in yeast. However, their role in autophagy has not been elucidated so far. In this article, the role of Mcp1, one core component of vCLAMP, in mitophagy of Candida albicans was investigated. Deletion of MCP1 led to abnormal accumulation of enlarged mitochondria and attenuated stability of mitochondrial DNA (mtDNA) in C. albicans when cultured in non-fermentable carbon sources. Furthermore, the mcp1Δ/Δ mutant exhibited defective growth and degradation of Csp37-GFP. These results indicate that Mcp1 plays a crucial role in mitophagy and maintenance of mitochondrial functions under the non-fermentable condition. Interestingly, this deletion had no impact on degradation of Atg8 (the macroautophagy reporter) and Lap41 (the cytoplasm-to-vacuole targeting pathway marker) under SD-N medium. Moreover, deletion of MCP1 inhibited filamentous growth and impaired virulence of the pathogen. This study provides an insight to vCLAMPs in cellular functions and pathogenicity in C. albicans.

scholarly journals Signal Peptide Hydrophobicity Modulates Interaction with the Twin-Arginine Translocase

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Qi Huang ◽  
Tracy Palmer
Keyword(s):  
Signal Peptide ◽  
Secretory Pathway ◽  
Recognition Site ◽  
Signal Peptides ◽  
Tat Pathway ◽  
Folded Proteins ◽  
Twin Arginine Translocase ◽  
Critical Requirement ◽  
Highly Hydrophobic ◽  
Peptide Hydrophobicity

ABSTRACT The general secretory pathway (Sec) and twin-arginine translocase (Tat) operate in parallel to export proteins across the cytoplasmic membrane of prokaryotes and the thylakoid membrane of plant chloroplasts. Substrates are targeted to their respective machineries by N-terminal signal peptides that share a tripartite organization; however, Tat signal peptides harbor a conserved and almost invariant arginine pair that is critical for efficient targeting to the Tat machinery. Tat signal peptides interact with a membrane-bound receptor complex comprised of TatB and TatC components, with TatC containing the twin-arginine recognition site. Here, we isolated suppressors in the signal peptide of the Tat substrate, SufI, that restored Tat transport in the presence of inactivating substitutions in the TatC twin-arginine binding site. These suppressors increased signal peptide hydrophobicity, and copurification experiments indicated that they restored binding to the variant TatBC complex. The hydrophobic suppressors could also act in cis to suppress substitutions at the signal peptide twin-arginine motif that normally prevent targeting to the Tat pathway. Highly hydrophobic variants of the SufI signal peptide containing four leucine substitutions retained the ability to interact with the Tat system. The hydrophobic signal peptides of two Sec substrates, DsbA and OmpA, containing twin lysine residues, were shown to mediate export by the Tat pathway and to copurify with TatBC. These findings indicate that there is unprecedented overlap between Sec and Tat signal peptides and that neither the signal peptide twin-arginine motif nor the TatC twin-arginine recognition site is an essential mechanistic feature for operation of the Tat pathway. IMPORTANCE Protein export is an essential process in all prokaryotes. The Sec and Tat export pathways operate in parallel, with the Sec machinery transporting unstructured precursors and the Tat pathway transporting folded proteins. Proteins are targeted to the Tat pathway by N-terminal signal peptides that contain an almost invariant twin-arginine motif. Here, we make the surprising discovery that the twin arginines are not essential for recognition of substrates by the Tat machinery and that this requirement can be bypassed by increasing the signal peptide hydrophobicity. We further show that signal peptides of bona fide Sec substrates can also mediate transport by the Tat pathway. Our findings suggest that key features of the Tat targeting mechanism have evolved to prevent mistargeting of substrates to the Sec pathway rather than being a critical requirement for function of the Tat pathway.

scholarly journals E-cadherin Beyond Structure: A Signaling Hub in Colon Homeostasis and Disease

2019 ◽  
Vol 20 (11) ◽  
pp. 2756 ◽  
Author(s):  
Amanda C. Daulagala ◽  
Mary Catherine Bridges ◽  
Antonis Kourtidis
Keyword(s):  
Cell Behavior ◽  
Colonic Epithelium ◽  
Core Component ◽  
Critical Function ◽  
The Core ◽  
Colon Tumorigenesis ◽  
Barrier Formation ◽  
Traditional Roles ◽  
E Cadherin

E-cadherin is the core component of epithelial adherens junctions, essential for tissue development, differentiation, and maintenance. It is also fundamental for tissue barrier formation, a critical function of epithelial tissues. The colon or large intestine is lined by an epithelial monolayer that encompasses an E-cadherin-dependent barrier, critical for the homeostasis of the organ. Compromised barriers of the colonic epithelium lead to inflammation, fibrosis, and are commonly observed in colorectal cancer. In addition to its architectural role, E-cadherin is also considered a tumor suppressor in the colon, primarily a result of its opposing function to Wnt signaling, the predominant driver of colon tumorigenesis. Beyond these well-established traditional roles, several studies have portrayed an evolving role of E-cadherin as a signaling epicenter that regulates cell behavior in response to intra- and extra-cellular cues. Intriguingly, these recent findings also reveal tumor-promoting functions of E-cadherin in colon tumorigenesis and new interacting partners, opening future avenues of investigation. In this Review, we focus on these emerging aspects of E-cadherin signaling, and we discuss their implications in colon biology and disease.

scholarly journals Signal peptide hydrophobicity modulates interaction with the twin-arginine translocase

2017 ◽  
Author(s):  
Qi Huang ◽  
Tracy Palmer
Keyword(s):  
Signal Peptide ◽  
Secretory Pathway ◽  
Recognition Site ◽  
Signal Peptides ◽  
Tat Pathway ◽  
Folded Proteins ◽  
Twin Arginine Translocase ◽  
Critical Requirement ◽  
Highly Hydrophobic ◽  
Peptide Hydrophobicity

AbstractThe general secretory pathway (Sec) and twin-arginine translocase (Tat) operate in parallel to export proteins across the cytoplasmic membrane of prokaryotes and the thylakoid membrane of plant chloroplasts. Substrates are targeted to their respective machineries by N-terminal signal peptides that share a common tripartite organization, however Tat signal peptides harbor a conserved and almost invariant arginine pair that are critical for efficient targeting to the Tat machinery. Tat signal peptides interact with a membrane-bound receptor complex comprised of TatB and TatC components, with TatC containing the twin-arginine recognition site. Here we isolated suppressors in the signal peptide of the Tat substrate, SufI, that restored Tat transport in the presence of inactivating substitutions in the TatC twin-arginine binding site. These suppressors increased signal peptide hydrophobicity, and co-purification experiments indicated that they restored binding to the variant TatBC complex. The hydrophobic suppressors could also act in cis to suppress substitutions at the signal peptide twin-arginine motif that normally prevent targeting to the Tat pathway. Highly hydrophobic variants of the SufI signal peptide containing four leucine substitutions retained the ability to interact with the Tat system. The hydrophobic signal peptides of two Sec substrates, DsbA and OmpA, containing twin lysine residues, were shown to mediate export by the Tat pathway and to co-purify with TatBC. These findings indicate that there is unprecedented overlap between Sec and Tat signal peptides and that neither the signal peptide twin-arginine motif nor the TatC twin-arginine recognition site are essential mechanistic features for operation of the Tat pathway.ImportanceProtein export is an essential process in all prokaryotes, The Sec and Tat export pathways operate in parallel, with the Sec machinery transporting unstructured precursors and the Tat pathway transporting folded proteins. Proteins are targeted to the Tat pathway by N-terminal signal peptides that contain an almost invariant twin-arginine motif. Here we make the surprising discovery that the twin-arginines are not essential for recognition of substrates by the Tat machinery, and that this requirement can be bypassed by increasing the signal peptide hydrophobicity. We further show that signal peptides of bona fide Sec substrates can also mediate transport by the Tat pathway. Our findings suggest that key features of the Tat targeting mechanism have evolved to prevent mis-targeting of substrates to the Sec pathway rather than being a critical requirement for function of the Tat pathway.

Does a Ribosome Really Read? On the Cognitive Roots and Heuristic Value of Linguistic Metaphors in Molecular Genetics. Part 2

2020 ◽  
Vol 63 (2) ◽  
pp. 46-62
Author(s):  
Suren T. Zolyan
Keyword(s):  
Information Processing ◽  
Genetic Information ◽  
Formal Organization ◽  
Dual Nature ◽  
Reading Frame ◽  
The Core ◽  
Genetic Information Processing ◽  
Cognitive Frame ◽  
Effective Instrument

We discuss the role of linguistic metaphors as a cognitive frame for the understanding of genetic information processing. The essential similarity between language and genetic information processing has been recognized since the very beginning, and many prominent scholars have noted the possibility of considering genes and genomes as texts or languages. Most of the core terms in molecular biology are based on linguistic metaphors. The processing of genetic information is understood as some operations on text – writing, reading and editing and their specification (encoding/decoding, proofreading, transcription, translation, reading frame). The concept of gene reading can be traced from the archaic idea of the equation of Life and Nature with the Book. Thus, the genetics itself can be metaphorically represented as some operations on text (deciphering, understanding, code-breaking, transcribing, editing, etc.), which are performed by scientists. At the same time linguistic metaphors portrayed gene entities also as having the ability of reading. In the case of such “bio-reading” some essential features similar to the processes of human reading can be revealed: this is an ability to identify the biochemical sequences based on their function in an abstract system and distinguish between type and its contextual tokens of the same type. Metaphors seem to be an effective instrument for representation, as they make possible a two-dimensional description: biochemical by its experimental empirical results and textual based on the cognitive models of comprehension. In addition to their heuristic value, linguistic metaphors are based on the essential characteristics of genetic information derived from its dual nature: biochemical by its substance, textual (or quasi-textual) by its formal organization. It can be concluded that linguistic metaphors denoting biochemical objects and processes seem to be a method of description and explanation of these heterogeneous properties.

Exploring the Mechanism of Lingzhu San in Treating Febrile Seizures by Using Network Pharmacology

2020 ◽  
Vol 23 ◽  
Author(s):  
Xiao Zhou ◽  
Xiao-Fei Zhang ◽  
Dong-Yan Guo ◽  
Yan-Jun Yang ◽  
Lin Liu ◽  
...  
Keyword(s):  
Febrile Seizures ◽  
Network Pharmacology ◽  
Biological Processes ◽  
Active Compounds ◽  
Potential Core ◽  
R Language ◽  
The Core ◽  
Multiple Factors ◽  
Therapeutic Mechanism

Objective: Lingzhu San (LZS) is a traditional Chinese medicine (TCM) prescription which can be effective in treating febrile seizures (FS) and has few researches on the mechanisms. In order to better guide the clinical use of LZS, we used the research ideas and methods of network pharmacology to find the potential core compounds, targets and pathways of LZS in the complex TCM system for the treatment of FS, and predict the mechanism. Materials and Methods: Databases such as BATMAN, TCMSP, TCMID, and SWISS TARGET are used to mine the active compounds and targets of LZS, and the target information of FS was obtained through GENECARDS and OMIM. Using Venny2.1.0 and Cytoscape software to locked the potential core compounds and targets of FS. The R language and ClusterProfiler software package were adopt to enrich and analyze the KEGG and GO pathways of the core targets and the biological processes and potential mechanisms of the core targets were revealed. Results: 187 active compounds and 2113 target proteins of LZS were collected. And 38 potential core compounds, 35 core targets and 775 metabolic and functional pathways were screened which involved in mediating FS. Finally, the role of the core compounds, targets and pivotal pathways of LZS regulated FS in the pathogenesis and therapeutic mechanism of FS was discussed and clarified. Conclusions: In this paper, the multi-compounds, multi-targets and multi-pathways mechanism of LZS in the treatment of FS was preliminarily revealed through the analysis of network pharmacology data, which is consistent with the principle of multi-compounds compatibility of TCM prescriptions and unified treatment of diseases from multiple angles, and it provides a new way for TCM to treat complex diseases caused by multiple factors.

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