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The very large G-protein-coupled receptor 1 (VLGR1/ADGRV1) is the largest member of the adhesion G-protein-coupled receptor (ADGR) family. Mutations in VLGR1/ADGRV1 cause human Usher syndrome (USH), a form of hereditary deaf-blindness, and have been additionally linked to epilepsy. In the absence of tangible knowledge of the molecular function and signaling of VLGR1, the pathomechanisms underlying the development of these diseases are still unknown. Our study aimed to identify novel, previously unknown protein networks associated with VLGR1 in order to describe new functional cellular modules of this receptor. Using affinity proteomics, we have identified numerous new potential binding partners and ligands of VLGR1. Tandem affinity purification hits were functionally grouped based on their Gene Ontology terms and associated with functional cellular modules indicative of functions of VLGR1 in transcriptional regulation, splicing, cell cycle regulation, ciliogenesis, cell adhesion, neuronal development, and retinal maintenance. In addition, we validated the identified protein interactions and pathways in vitro and in situ. Our data provided new insights into possible functions of VLGR1, related to the development of USH and epilepsy, and also suggest a possible role in the development of other neuronal diseases such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Adhesion G protein-coupled receptors (ADGRs) have recently become a target of intense research. Their unique protein structure, which consists of a G protein-coupled receptor combined with long adhesive extracellular domains, suggests a dual role in cell signaling and adhesion. Despite considerable progress in the understanding of ADGR signaling over the past years, the knowledge about ADGR protein networks is still limited. For most receptors, only a few interaction partners are known thus far. We aimed to identify novel ADGR-interacting partners to shed light on cellular protein networks that rely on ADGR function. For this, we applied affinity proteomics, utilizing tandem affinity purifications combined with mass spectrometry. Analysis of the acquired proteomics data provides evidence thatADGRs not only have functional roles at synapses but also at intracellularmembranes, namely at the endoplasmic reticulum, theGolgi apparatus, mitochondria, and mitochondria-associatedmembranes (MAMs). Specifically, we found an association ofADGRswith several scaffold proteins of themembrane-associated guanylate kinases family, elementary units of the γ-secretase complex, the outer/innermitochondrial membrane,MAMs, and regulators of the Wnt signaling pathways. Furthermore, the nuclear localization of ADGR domains together with their physical interaction with nuclear proteins and several transcription factors suggests a role of ADGRs in gene regulation. [ABSTRACT FROM AUTHOR]

The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse, zebrafish and nematode) and techniques. For example, we show that OSCP1, which has previously been implicated in two distinct non-ciliary processes, causes ciliogenic and ciliopathy-associated tissue phenotypes when depleted in zebrafish. The candidate list forms the basis of CiliaCarta, a comprehensive ciliary compendium covering 956 genes. The resource can be used to objectively prioritize candidate genes in whole exome or genome sequencing of ciliopathy patients and can be accessed at . [ABSTRACT FROM AUTHOR]

I received my copy of Michigan History Magazine and was pleased to see the story of my grandfather Charles Dewitt Hammond featured (M/J 2000). My father, Nathan L. Hammond, who […]

A correction to the article "The Psychology of Sport and Physical Activity," that was published in the previous issue is presented.

Summarizes a study about adult gaze and affective and visual responses of preschool children. Subjects of the study; Results.

The human Usher syndrome (USH) is a retinal ciliopathy, characterized by profound congenital deafness, variable vestibular dysfunction and pre-pubertal onset of retinitis pigmentosa. In the effected sensory cells, USH protein networks are assumed to function in ciliary transport processes. The USH1G protein SANS is a scaffold of the ciliary/periciliary USH protein network of photoreceptor cells. Moreover, SANS is associated with microtubules, the transport routes for protein delivery toward the cilium. To enlighten the role of SANS in ciliary transport processes, we aimed to identify transport related proteins associated with SANS. The intraflagellar transport (IFT) system is a conserved mechanism for bi-directional transport toward and through primary cilia. Thus, we tested the direct binding of SANS to IFT molecules, namely IFT20, IFT57, and IFT74 in 1:1 yeast-two-hybrid assay. The identified SANS-IFT interactions were validated in vitro via independent complementary interaction assays and in cells by applying membrane targeting assays. Quantitative immunofluorescence microscopy revealed the co-localization of SANS with IFT20, IFT52, and IFT57 particularly at ciliary base of wild type mouse photoreceptor cells. Analysis of photoreceptor cells of SANS knock out mice revealed the decrease of IFTs in the ciliary compartment indicating a role of SANS in the proper positioning of IFT-B molecules in primary cilia. Our study demonstrated direct binding of IFT complex B proteins IFT52 and IFT57 to the N-terminal ankyrin repeats and the central domain of SANS. Our data also indicate that pathologic mutations in the N-terminus of SANS lead to the loos of SANS binding to IFT-B molecules. Our findings provide direct evidence for a molecular link between the ciliary USH protein network and the IFT transport module in primary cilia., (Copyright © 2019 Sorusch, Yildirim, Knapp, Janson, Fleck, Scharf and Wolfrum.)

Adhesion G protein-coupled receptors (aGPCRs/ADGRs) are unique receptors that combine cell adhesion and signaling functions. Protein networks related to ADGRs exert diverse functions, e.g., in tissue polarity, cell migration, nerve cell function, or immune response, and are regulated via different mechanisms. The large extracellular domain of ADGRs is capable of mediating cell-cell or cell-matrix protein interactions. Their intracellular surface and domains are coupled to downstream signaling pathways and often bind to scaffold proteins, organizing membrane-associated protein complexes. The cohesive interplay between ADGR-related network components is essential to prevent severe disease-causing damage in numerous cell types. Consequently, in recent years, attention has focused on the decipherment of the precise molecular composition of ADGR protein complexes and interactomes in various cellular modules. In this chapter, we discuss the affiliation of ADGR networks to cellular modules and how they can be regulated, pinpointing common features in the networks related to the diverse ADGRs. Detailed decipherment of the composition of protein networks should provide novel targets for the development of novel therapies with the aim to cure human diseases related to ADGRs.

The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADGRG1 (GPR56), ADGRG2 (GPR64, HE6), ADGRG3 (GPR97), ADGRG4 (GPR112), ADGRG5 (GPR114), ADGRG6 (GPR126), ADGRG7 (GPR128), ADGRL1 (latrophilin-1, CIRL-1, CL1), ADGRL2 (latrophilin-2, CIRL-2, CL2), ADGRL3 (latrophilin-3, CIRL-3, CL3), ADGRL4 (ELTD1, ETL), and ADGRV1 (VLGR1, GPR98). This review covers all major biologic aspects of Adhesion GPCRs, including evolutionary origins, interaction partners, signaling, expression, physiologic functions, and therapeutic potential., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)