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Nature Jan 2024Chemical signalling is the primary means by which cells communicate in the embryo. The underlying principle refers to a group of ligand-producing cells and a group of...
Chemical signalling is the primary means by which cells communicate in the embryo. The underlying principle refers to a group of ligand-producing cells and a group of cells that respond to this signal because they express the appropriate receptors. In the zebrafish embryo, Wnt5b binds to the receptor Ror2 to trigger the Wnt-planar cell polarity (PCP) signalling pathway to regulate tissue polarity and cell migration. However, it remains unclear how this lipophilic ligand is transported from the source cells through the aqueous extracellular space to the target tissue. In this study, we provide evidence that Wnt5b, together with Ror2, is loaded on long protrusions called cytonemes. Our data further suggest that the active Wnt5b-Ror2 complexes form in the producing cell and are handed over from these cytonemes to the receiving cell. Then, the receiving cell has the capacity to initiate Wnt-PCP signalling, irrespective of its functional Ror2 receptor status. On the tissue level, we further show that cytoneme-dependent spreading of active Wnt5b-Ror2 affects convergence and extension in the zebrafish gastrula. We suggest that cytoneme-mediated transfer of ligand-receptor complexes is a vital mechanism for paracrine signalling. This may prompt a reevaluation of the conventional concept of characterizing responsive and non-responsive tissues solely on the basis of the expression of receptors.
Topics: Animals; Gastrula; Ligands; Wnt Proteins; Wnt Signaling Pathway; Zebrafish; Cell Polarity; Cell Movement; Pseudopodia; Receptor Tyrosine Kinase-like Orphan Receptors; Paracrine Communication
PubMed: 38123680
DOI: 10.1038/s41586-023-06850-7 -
Nature Communications Jul 2023Multiple SARS-CoV-2 Omicron sub-variants, such as BA.2, BA.2.12.1, BA.4, and BA.5, emerge one after another. BA.5 has become the dominant strain worldwide. Additionally,...
Multiple SARS-CoV-2 Omicron sub-variants, such as BA.2, BA.2.12.1, BA.4, and BA.5, emerge one after another. BA.5 has become the dominant strain worldwide. Additionally, BA.2.75 is significantly increasing in some countries. Exploring their receptor binding and interspecies transmission risk is urgently needed. Herein, we examine the binding capacities of human and other 28 animal ACE2 orthologs covering nine orders towards S proteins of these sub-variants. The binding affinities between hACE2 and these sub-variants remain in the range as that of previous variants of concerns (VOCs) or interests (VOIs). Notably, R493Q reverse mutation enhances the bindings towards ACE2s from humans and many animals closely related to human life, suggesting an increased risk of cross-species transmission. Structures of S/hACE2 or RBD/hACE2 complexes for these sub-variants and BA.2 S binding to ACE2 of mouse, rat or golden hamster are determined to reveal the molecular basis for receptor binding and broader interspecies recognition.
Topics: Cricetinae; Humans; Animals; Mice; Rats; Angiotensin-Converting Enzyme 2; COVID-19; SARS-CoV-2; Mesocricetus; Mutation
PubMed: 37479708
DOI: 10.1038/s41467-023-39942-z -
Biomolecules Apr 2024Tumor necrosis factor receptor-associated factor (TRAF) proteins play pivotal roles in a multitude of cellular signaling pathways, encompassing immune response, cell... (Review)
Review
Tumor necrosis factor receptor-associated factor (TRAF) proteins play pivotal roles in a multitude of cellular signaling pathways, encompassing immune response, cell fate determination, development, and thrombosis. Their involvement in these processes hinges largely on their ability to interact directly with diverse receptors via the TRAF domain. Given the limited binding interface, understanding how specific TRAF domains engage with various receptors and how structurally similar binding interfaces of TRAF family members adapt their distinct binding partners has been the subject of extensive structural investigations over several decades. This review presents an in-depth exploration of the current insights into the structural and molecular diversity exhibited by the TRAF domain and TRAF-binding motifs across a range of receptors, with a specific focus on TRAF1.
Topics: Humans; TNF Receptor-Associated Factor 1; Animals; Protein Binding; Signal Transduction; Protein Domains; Models, Molecular
PubMed: 38785916
DOI: 10.3390/biom14050510 -
BMB Reports Oct 2023Serotonin receptors, also known as 5-HT receptors, belong to the G protein-coupled receptors (GPCRs) superfamily. They mediate the effects of serotonin, a... (Review)
Review
Serotonin receptors, also known as 5-HT receptors, belong to the G protein-coupled receptors (GPCRs) superfamily. They mediate the effects of serotonin, a neurotransmitter that plays a key role in a wide range of functions including mood regulation, cognition and appetite. The functions of serotonin are mediated by a family of 5-HT receptors including 12 GPCRs belonging to six major families: 5-HT, 5-HT, 5-HT, 5-HT, 5-HT and 5-HT. Despite their distinct characteristics and functions, these receptors' subtypes share common structural features and signaling mechanisms. Understanding the structure, functions and pharmacology of the serotonin receptor family is essential for unraveling the complexities of serotonin signaling and developing targeted therapeutics for neuropsychiatric disorders. However, developing drugs that selectively target specific receptor subtypes is challenging due to the structural similarities in their orthosteric binding sites. This review focuses on the recent advancements in the structural studies of 5-HT receptors, highlighting the key structural features of each subtype and shedding light on their potential as targets for mental health and neurological disorders (such as depression, anxiety, schizophrenia, and migraine) drugs. [BMB Reports 2023; 56(10): 527-536].
Topics: Serotonin; Receptors, Serotonin; Binding Sites
PubMed: 37817438
DOI: 10.5483/BMBRep.2023-0147 -
The Journal of Biological Chemistry Oct 2023Dihydroxy acid leukotriene (LTB) and cysteinyl leukotrienes (LTC, LTD, and LTE) are inflammatory mediators derived from arachidonic acid via the 5-lipoxygenase pathway.... (Review)
Review
Dihydroxy acid leukotriene (LTB) and cysteinyl leukotrienes (LTC, LTD, and LTE) are inflammatory mediators derived from arachidonic acid via the 5-lipoxygenase pathway. While structurally similar, these two types of leukotrienes (LTs) exert their functions through interactions with two distinct G protein-coupled receptor (GPCR) families, BLT and CysLT receptors, which share low sequence similarity and belong to phylogenetically divergent GPCR groups. Selective antagonism of LT receptors has been proposed as a promising strategy for the treatment of many inflammation-related diseases including asthma and chronic obstructive pulmonary disease, rheumatoid arthritis, cystic fibrosis, diabetes, and several types of cancer. Selective CysLTR antagonists are currently used as antiasthmatic drugs, however, there are no approved drugs targeting CysLT and BLT receptors. In this review, we highlight recently published structures of BLTR and CysLTRs revealing unique structural features of the two receptor families. X-ray and cryo-EM data shed light on their overall conformations, differences in functional motifs involved in receptor activation, and details of the ligand-binding pockets. An unexpected binding mode of the selective antagonist BIIL260 in the BLTR structure makes it the first example of a compound targeting the sodium-binding site of GPCRs and suggests a novel strategy for the receptor activity modulation. Taken together, these recent structural data reveal dramatic differences in the molecular architecture of the two LT receptor families and pave the way to new therapeutic strategies of selective targeting individual receptors with novel tool compounds obtained by the structure-based drug design approach.
PubMed: 37703990
DOI: 10.1016/j.jbc.2023.105247 -
International Journal of Oral Science Aug 2023Orthodontically induced tooth root resorption (OIRR) is a serious complication during orthodontic treatment. Stimulating cementum repair is the fundamental approach for...
Orthodontically induced tooth root resorption (OIRR) is a serious complication during orthodontic treatment. Stimulating cementum repair is the fundamental approach for the treatment of OIRR. Parathyroid hormone (PTH) might be a potential therapeutic agent for OIRR, but its effects still lack direct evidence, and the underlying mechanisms remain unclear. This study aims to explore the potential involvement of long noncoding RNAs (lncRNAs) in mediating the anabolic effects of intermittent PTH and contributing to cementum repair, as identifying lncRNA-disease associations can provide valuable insights for disease diagnosis and treatment. Here, we showed that intermittent PTH regulates cell proliferation and mineralization in immortalized murine cementoblast OCCM-30 via the regulation of the Wnt pathway. In vivo, daily administration of PTH is sufficient to accelerate root regeneration by locally inhibiting Wnt/β-catenin signaling. Through RNA microarray analysis, lncRNA LITTIP (LGR6 intergenic transcript under intermittent PTH) is identified as a key regulator of cementogenesis under intermittent PTH. Chromatin isolation by RNA purification (ChIRP) and RNA immunoprecipitation (RIP) assays revealed that LITTIP binds to mRNA of leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) and heterogeneous nuclear ribonucleoprotein K (HnRNPK) protein. Further co-transfection experiments confirmed that LITTIP plays a structural role in the formation of the LITTIP/Lgr6/HnRNPK complex. Moreover, LITTIP is able to promote the expression of LGR6 via the RNA-binding protein HnRNPK. Collectively, our results indicate that the intermittent PTH administration accelerates root regeneration via inhibiting Wnt pathway. The lncRNA LITTIP is identified to negatively regulate cementogenesis, which activates Wnt/β-catenin signaling via high expression of LGR6 promoted by HnRNPK.
Topics: Mice; Animals; Cementogenesis; Wnt Signaling Pathway; beta Catenin; Heterogeneous-Nuclear Ribonucleoprotein K; RNA, Long Noncoding; Parathyroid Hormone; Receptors, G-Protein-Coupled
PubMed: 37558690
DOI: 10.1038/s41368-023-00237-0