scholarly journals Wnt3 Is Lipidated at Conserved Cysteine and Serine Residues in Zebrafish Neural Tissue

2021 ◽  
Vol 9 ◽  
Author(s):  
Divya Dhasmana ◽  
Sapthaswaran Veerapathiran ◽  
Yagmur Azbazdar ◽  
Ashwin Venkata Subba Nelanuthala ◽  
Cathleen Teh ◽  
...  
Keyword(s):  
Receptor Interaction ◽  
Lipid Domains ◽  
Membrane Organization ◽  
Conserved Residues ◽  
Physiological Processes ◽  
Wnt Proteins ◽  
Neural Tissues ◽  
Wnt Ligands ◽  
Open Question ◽  
Interaction With Receptors

Wnt proteins are a family of hydrophobic cysteine-rich secreted glycoproteins that regulate a gamut of physiological processes involved in embryonic development and tissue homeostasis. Wnt ligands are post-translationally lipidated in the endoplasmic reticulum (ER), a step essential for its membrane targeting, association with lipid domains, secretion and interaction with receptors. However, at which residue(s) Wnts are lipidated remains an open question. Initially it was proposed that Wnts are lipid-modified at their conserved cysteine and serine residues (C77 and S209 in mWnt3a), and mutations in either residue impedes its secretion and activity. Conversely, some studies suggested that serine is the only lipidated residue in Wnts, and substitution of serine with alanine leads to retention of Wnts in the ER. In this work, we investigate whether in zebrafish neural tissues Wnt3 is lipidated at one or both conserved residues. To this end, we substitute the homologous cysteine and serine residues of zebrafish Wnt3 with alanine (C80A and S212A) and investigate their influence on Wnt3 membrane organization, secretion, interaction and signaling activity. Collectively, our results indicate that Wnt3 is lipid modified at its C80 and S212 residues. Further, we find that lipid addition at either C80 or S212 is sufficient for its secretion and membrane organization, while the lipid modification at S212 is indispensable for receptor interaction and signaling.

scholarly journals Generating a Wnt switch: it’s all about the right dosage

2011 ◽  
Vol 193 (3) ◽  
pp. 431-433 ◽  
Author(s):  
Hans A. Kestler ◽  
Michael Kühl
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Wnt Proteins ◽  
Cell Biol ◽  
Tissue Patterning ◽  
Wnt Ligands ◽  
The Right

Wnt proteins can activate different branches of the Wnt signaling pathway, raising the question of specificity. In this issue, Nalesso et al. (2011. J. Cell Biol. doi:10.1083/jcb.201011051) provide an answer to this conundrum by showing that different concentrations of Wnt ligands can elicit different intracellular responses. These findings not only provide new insights into the molecular mechanisms underlying Wnt signaling, but also indicate how Wnt gradients might contribute to tissue patterning during embryogenesis.

scholarly journals Gene activation and repression by the glucocorticoid receptor are mediated by sequestering Ep300 and two modes of chromatin binding

2019 ◽  
Author(s):  
Avital Sarusi Portuguez ◽  
Ivana Grbesa ◽  
Moran Tal ◽  
Rachel Deitch ◽  
Dana Raz ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Binding Sites ◽  
Gene Activation ◽  
Spatial Separation ◽  
Regulatory Elements ◽  
Chromatin Interaction ◽  
Chromatin Binding ◽  
Physiological Processes ◽  
Regulatory Loci ◽  
Open Question

ABSTRACTThe transcription factor glucocorticoid receptor (GR) is a key mediator of stress response and a broad range of physiological processes. How can GR rapidly activate the expression of some genes while repress others, remains an open question due to the challenge to associate GR binding sites (GBSs) to their distant gene targets. Mapping the full 3D scope of GR-responsive promoters using high-resolution 4C-seq unravelled spatial separation between chromatin interaction networks of GR-activated and repressed genes. Analysing GR binding sites and other regulatory loci in their functional 3D context revealed that GR sequesters the co-activator Ep300 from active non-GBS enhancers in both activated and repressed gene compartments. While this is sufficient for rapid gene repression, gene activation is countered by productive recruitment of Ep300 to GBS. Importantly, in GR-activated compartments Klf4 binding at non-GBS regulatory elements cluster in 3D with GBS and antagonizes GR activation. In addition, we revealed ROR and Rev-erb transcription factors as novel co-regulators for GR-mediated gene expression.

scholarly journals Capturing Peptide–GPCR Interactions and Their Dynamics

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4724
Author(s):  
Anette Kaiser ◽  
Irene Coin
Keyword(s):  
Ligand Binding ◽  
Conformational Changes ◽  
Structural Changes ◽  
Structural Heterogeneity ◽  
Receptor Interaction ◽  
Spectroscopic Techniques ◽  
Peptide Receptors ◽  
Physiological Processes ◽  
High Dynamics ◽  
G Protein Coupled

Many biological functions of peptides are mediated through G protein-coupled receptors (GPCRs). Upon ligand binding, GPCRs undergo conformational changes that facilitate the binding and activation of multiple effectors. GPCRs regulate nearly all physiological processes and are a favorite pharmacological target. In particular, drugs are sought after that elicit the recruitment of selected effectors only (biased ligands). Understanding how ligands bind to GPCRs and which conformational changes they induce is a fundamental step toward the development of more efficient and specific drugs. Moreover, it is emerging that the dynamic of the ligand–receptor interaction contributes to the specificity of both ligand recognition and effector recruitment, an aspect that is missing in structural snapshots from crystallography. We describe here biochemical and biophysical techniques to address ligand–receptor interactions in their structural and dynamic aspects, which include mutagenesis, crosslinking, spectroscopic techniques, and mass-spectrometry profiling. With a main focus on peptide receptors, we present methods to unveil the ligand–receptor contact interface and methods that address conformational changes both in the ligand and the GPCR. The presented studies highlight a wide structural heterogeneity among peptide receptors, reveal distinct structural changes occurring during ligand binding and a surprisingly high dynamics of the ligand–GPCR complexes.

scholarly journals Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding?

Biomolecules ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 94 ◽  
Author(s):  
Hélène Pollet ◽  
Louise Conrard ◽  
Anne-Sophie Cloos ◽  
Donatienne Tyteca
Keyword(s):  
Plasma Membrane ◽  
Membrane Lipids ◽  
Disease Diagnosis ◽  
Membrane Lipid ◽  
Lipid Domains ◽  
Disease Evolution ◽  
Physiological Processes ◽  
Plasma Membrane Lipid ◽  
Vesicle Biogenesis ◽  
Few Data

Extracellular vesicles (EVs) contribute to several pathophysiological processes and appear as emerging targets for disease diagnosis and therapy. However, successful translation from bench to bedside requires deeper understanding of EVs, in particular their diversity, composition, biogenesis and shedding mechanisms. In this review, we focus on plasma membrane-derived microvesicles (MVs), far less appreciated than exosomes. We integrate documented mechanisms involved in MV biogenesis and shedding, focusing on the red blood cell as a model. We then provide a perspective for the relevance of plasma membrane lipid composition and biophysical properties in microvesiculation on red blood cells but also platelets, immune and nervous cells as well as tumor cells. Although only a few data are available in this respect, most of them appear to converge to the idea that modulation of plasma membrane lipid content, transversal asymmetry and lateral heterogeneity in lipid domains may play a significant role in the vesiculation process. We suggest that lipid domains may represent platforms for inclusion/exclusion of membrane lipids and proteins into MVs and that MVs could originate from distinct domains during physiological processes and disease evolution.

scholarly journals Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Vu Hong Loan Nguyen ◽  
Rebecca Hough ◽  
Stefanie Bernaudo ◽  
Chun Peng
Keyword(s):  
Ovarian Cancer ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Self Renewal ◽  
Physiological Processes ◽  
Wnt Ligands ◽  
Non Coding Rnas ◽  
Strong Candidate ◽  
And Function ◽  
Intracellular Mediators

AbstractEpithelial ovarian cancer (EOC) is the deadliest female malignancy. The Wnt/β-catenin pathway plays critical roles in regulating embryonic development and physiological processes. This pathway is tightly regulated to ensure its proper activity. In the absence of Wnt ligands, β-catenin is degraded by a destruction complex. When the pathway is stimulated by a Wnt ligand, β-catenin dissociates from the destruction complex and translocates into the nucleus where it interacts with TCF/LEF transcription factors to regulate target gene expression. Aberrant activation of this pathway, which leads to the hyperactivity of β-catenin, has been reported in ovarian cancer. Specifically, mutations of CTNNB1, AXIN, or APC, have been observed in the endometrioid and mucinous subtypes of EOC. In addition, upregulation of the ligands, abnormal activation of the receptors or intracellular mediators, disruption of the β-catenin destruction complex, inhibition of the association of β-catenin/E-cadherin on the cell membrane, and aberrant promotion of the β-catenin/TCF transcriptional activity, have all been reported in EOC, especially in the high grade serous subtype. Furthermore, several non-coding RNAs have been shown to regulate EOC development, in part, through the modulation of Wnt/β-catenin signalling. The Wnt/β-catenin pathway has been reported to promote cancer stem cell self-renewal, metastasis, and chemoresistance in all subtypes of EOC. Emerging evidence also suggests that the pathway induces ovarian tumor angiogenesis and immune evasion. Taken together, these studies demonstrate that the Wnt/β-catenin pathway plays critical roles in EOC development and is a strong candidate for the development of targeted therapies.

Abstract 653: The Role of "Saposin-Like Domain" in Wnt Signaling

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Aparna Krishnamoorthy
Keyword(s):  
Wnt Signaling ◽  
Conformational Change ◽  
Membrane Surface ◽  
Critical Role ◽  
Gene Activation ◽  
Wnt Signaling Pathway ◽  
Lipid Binding ◽  
Water Soluble ◽  
Receptor Interaction ◽  
Wnt Proteins

Hyperlipidemia is a major contributor to atherosclerosis that results in endothelial dysfunction and is driven by several cell types including macrophages and vascular smooth muscle cells. Among the various cytokines and signaling molecules that contribute to the disease, dysregulated Wnt signaling is known to result in uncontrolled cell division within bulging aortic plaques. Wnt proteins are morphogens that signal through interactions with two membrane bound co-receptors: Frizzled and Low-density lipoprotein receptor related protein 5/6. Wnt binding to these receptors transduces a signal, leading to increased cellular levels of ß-catenin that migrates to the nucleus and leads to gene activation. Normally ß-catenin is rapidly degraded, a process that attenuates Wnt signaling. However, in many diseases, including atherosclerosis, ß-catenin levels remain elevated leading to uncontrolled activation of the Wnt pathway genes. Interestingly, while the intracellular events of the Wnt signaling pathway are well studied, questions about how a hydrophobic molecule like Wnt engages with cell surface receptors remain unexplored in the field. A recent X-ray crystal structure revealed Wnt exists as a two-domain protein: a C-terminal “cytokine like domain” and an N-terminal “saposin-like domain” that contains a covalently bound fatty acid. Saposins are a family of proteins that possess membrane / lipid binding properties and undergo a conformational change when they contact membrane surfaces. My hypothesis is that the saposin-like domain is a membrane active component that plays a critical role in initiating Wnt signaling by undergoing a conformational change upon reaching cell membrane in order to promote Wnt-receptor engagement and signaling. I plan to isolate and express the saposin-like domain, which will exist as a water-soluble helical bundle in the absence of lipid. When presented with an appropriate lipid surface, the saposin-like domain will unfurl, thereby exposing a hydrophobic interior that contacts the membrane surface. The ability of the isolated domain to interfere with Wnt signaling will also be determined. Findings from my study reveal the molecular basis underlying initial events of Wnt receptor interaction in atherosclerosis.

Secretin, at the hub of water-salt homeostasis

2017 ◽  
Vol 312 (5) ◽  
pp. F852-F860 ◽  
Author(s):  
Jenny Juan Bai ◽  
Chong Da Tan ◽  
Billy K. C. Chow
Keyword(s):  
Central Nervous System ◽  
Extracellular Fluid ◽  
Receptor Interaction ◽  
Gastrointestinal Hormone ◽  
Physiological Processes ◽  
Osmotic Homeostasis ◽  
Water Salt ◽  
The Central Nervous System ◽  
Salt Homeostasis

Water and salt metabolism are tightly regulated processes. Maintaining this milieu intérieur within narrow limits is critical for normal physiological processes to take place. Disturbances to this balance can result in disease and even death. Some of the better-characterized regulators of water and salt homeostasis include angiotensin II, aldosterone, arginine vasopressin, and oxytocin. Although secretin (SCT) was first described >100 years ago, little is known about the role of this classic gastrointestinal hormone in the maintenance of water-salt homeostasis. In recent years, increasing body of evidence suggested that SCT and its receptor play important roles in the central nervous system and kidney to ensure that the mammalian extracellular fluid osmolarity is kept within a healthy range. In this review, we focus on recent advances in our understanding of the molecular, cellular, and network mechanisms by which SCT and its receptor mediate the control of osmotic homeostasis. Implications of hormonal cross talk and receptor-receptor interaction are highlighted.

scholarly journals Xenopus Wntless and the Retromer Complex Cooperate To Regulate XWnt4 Secretion

2009 ◽  
Vol 29 (8) ◽  
pp. 2118-2128 ◽  
Author(s):  
Hyunjoon Kim ◽  
Seong-Moon Cheong ◽  
Jihae Ryu ◽  
Hwa-Jin Jung ◽  
Eek-hoon Jho ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Eye Development ◽  
Transmembrane Protein ◽  
Neural Induction ◽  
Neural Tube Closure ◽  
Mesoderm Induction ◽  
Wnt Proteins ◽  
Retromer Complex ◽  
Evolutionarily Conserved ◽  
Wnt Ligands

ABSTRACT Wnt signaling is implicated in a variety of developmental and pathological processes. The molecular mechanisms governing the secretion of Wnt ligands remain to be elucidated. Wntless, an evolutionarily conserved multipass transmembrane protein, is a dedicated secretion factor of Wnt proteins that participates in Drosophila melanogaster embryogenesis. In this study, we show that Xenopus laevis Wntless (XWntless) regulates the secretion of a specific Wnt ligand, XWnt4, and that this regulation is specifically required for eye development in Xenopus. Moreover, the Retromer complex is required for XWntless recycling to regulate the XWnt4-mediated eye development. Inhibition of Retromer function by Vps35 morpholino (MO) resulted in various Wnt deficiency phenotypes, affecting mesoderm induction, gastrulation cell movements, neural induction, neural tube closure, and eye development. Overexpression of XWntless led to the rescue of Vps35 MO-mediated eye defects but not other deficiencies. These results collectively suggest that XWntless and the Retromer complex are required for the efficient secretion of XWnt4, facilitating its role in Xenopus eye development.

scholarly journals A Zic2-regulated switch in a noncanonical Wnt/βcatenin pathway is essential for the formation of bilateral circuits

2020 ◽  
Vol 6 (46) ◽  
pp. eaaz8797
Author(s):  
Cruz Morenilla-Palao ◽  
María Teresa López-Cascales ◽  
José P. López-Atalaya ◽  
Diana Baeza ◽  
Luís Calvo-Díaz ◽  
...  
Keyword(s):  
Wnt Pathway ◽  
Molecular Mechanisms ◽  
Optic Chiasm ◽  
Biological Processes ◽  
Axon Extension ◽  
Retinal Axons ◽  
Wnt Proteins ◽  
Intracellular Proteins ◽  
Wnt Ligands ◽  
Asymmetric Activation

The Wnt pathway is involved in a wide array of biological processes during development and is deregulated in many pathological scenarios. In neurons, Wnt proteins promote both axon extension and repulsion, but the molecular mechanisms underlying these opposing axonal responses are unknown. Here, we show that Wnt5a is expressed at the optic chiasm midline and promotes the crossing of retinal axons by triggering an alternative Wnt pathway that depends on the accumulation of βcatenin but does not activate the canonical pathway. In ipsilateral neurons, the transcription factor Zic2 switches this alternative Wnt pathway by regulating the expression of a set of Wnt receptors and intracellular proteins. In combination with this alternative Wnt pathway, the asymmetric activation of EphB1 receptors at the midline phosphorylates βcatenin and elicits a repulsive response. This alternative Wnt pathway and its Zic2-triggered switch may operate in other contexts that require a two-way response to Wnt ligands.

scholarly journals The physiological correlates of interpersonal space

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michela Candini ◽  
Simone Battaglia ◽  
Mariagrazia Benassi ◽  
Giuseppe di Pellegrino ◽  
Francesca Frassinetti
Keyword(s):  
Social Interactions ◽  
Skin Conductance Response ◽  
Warning Signal ◽  
The Body ◽  
Interpersonal Distance ◽  
Functional Link ◽  
Physiological Processes ◽  
Open Question ◽  
Healthy Participants ◽  
Interpersonal Space

AbstractInterpersonal space (IPS) is the area around the body that individuals maintain between themselves and others during social interactions. When others violate our IPS, feeling of discomfort rise up, urging us to move farther away and reinstate an appropriate interpersonal distance. Previous studies showed that when individuals are exposed to closeness of an unknown person (a confederate), the skin conductance response (SCR) increases. However, if the SCR is modulated according to participant’s preferred IPS is still an open question. To test this hypothesis, we recorded the SCR in healthy participants when a confederate stood in front of them at various distances simulating either an approach or withdrawal movement (Experiment 1). Then, the comfort-distance task was adopted to measure IPS: participants stop the confederate, who moved either toward or away from them, when they felt comfortable with other’s proximity (Experiment 2). We found higher SCR when the confederate stood closer to participants simulating an IPS intrusion, compared to when the confederate moved farther away. Crucially, we provide the first evidence that SCR, acting as a warning signal, contributes to interpersonal distance preference suggesting a functional link between behavioral components of IPS regulation and the underlying physiological processes.

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