Structure and evolution of neuronal wiring receptors and ligands

Developmental Dynamics, Год журнала: 2022, Номер 252(1), С. 27 - 60

Опубликована: Июнь 21, 2022

One of the fundamental properties a neuronal circuit is map its connections. The cellular and developmental processes that allow for growth axons dendrites, selection synaptic targets, formation functional synapses use surface receptors their interactions with other receptors, secreted ligands, matrix molecules. Spatiotemporal regulation expression these cues allows specificity in pathways wire stereotyped circuits. families molecules controlling axon guidance synapse are generally conserved across animals, some important exceptions, which have consequences connectivity. Here, we summarize distribution such multiple taxa, focus on model organisms, evolutionary led to multitude molecules, diversification or loss receptors.

Язык: Английский

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Mechanism of 5-fluorouracil induced resistance and role of piperine and curcumin as chemo-sensitizers in colon cancer

Naunyn-Schmiedeberg s Archives of Pharmacology, Год журнала: 2024, Номер unknown

Опубликована: Июнь 15, 2024

Язык: Английский

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Combinatorial expression of neurexins and LAR-type phosphotyrosine phosphatase receptors instructs assembly of a cerebellar circuit

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Авг. 17, 2023

Abstract Synaptic adhesion molecules (SAMs) shape the structural and functional properties of synapses thereby control information processing power neural circuits. SAMs are broadly expressed in brain, suggesting that they may instruct synapse formation specification via a combinatorial logic. Here, we generate sextuple conditional knockout mice targeting all members two major families presynaptic SAMs, Neurexins leukocyte common antigen-related-type receptor phospho-tyrosine phosphatases (LAR-PTPRs), which together account for majority known trans-synaptic complexes. Using formed by cerebellar Purkinje cells onto deep nuclei as model system, confirm LAR-PTPRs themselves not essential assembly. The deletion both neurexins LAR-PTPRs, however, decreases Purkinje-cell on nuclei, output pathway Consistent with this finding, combined but separate deletions impair motor behaviors. Thus, required assembly circuit.

Язык: Английский

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A mismatch in the expression of cell surface molecules induces tissue-intrinsic defense against aberrant cells

Current Biology, Год журнала: 2024, Номер 34(5), С. 980 - 996.e6

Опубликована: Фев. 12, 2024

Tissue-intrinsic error correction enables epithelial cells to detect abnormal neighboring and facilitate their removal from the tissue. One of these pathways, "interface surveillance," is triggered by with aberrant developmental cell-fate-patterning pathways. It remains unknown which molecular mechanisms provide ability compare fate between cells. We demonstrate that Drosophila imaginal discs express an array cell surface molecules previously implicated in neuronal axon guidance processes. They include members Robo, Teneurin, Ephrin, Toll-like, or atypical cadherin families. Importantly, a mismatch expression levels adjacent sufficient induce interface surveillance, indicating differences cells, rather than absolute levels, are crucial. Specifically, Robo2 Robo3, but not Robo1, induces enrichment actin, myosin II, Ena/Vasp, as well activation JNK apoptosis at clonal interfaces. Moreover, can surveillance independently its cytosolic domain without need for Robo-ligand Slit. The other molecules, such Teneurins Ephrin receptor regulated fate-patterning pathways intrinsic extrinsic wing disc, oncogenic RasV12. Combined, we respond code patterns mediated specific transmembrane proteins reveal novel function recognition during development homeostasis tissues.

Язык: Английский

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Structural insights into the formation of repulsive netrin guidance complexes

Science Advances, Год журнала: 2024, Номер 10(7)

Опубликована: Фев. 16, 2024

Netrins dictate attractive and repulsive responses during axon growth cell migration, where the presence of receptor Uncoordinated-5 (UNC-5) on target cells results in repulsion. Here, we showed that UNC-5 is a heparin-binding protein, determined its structure bound to heparin fragment, could modulate UNC-5–heparin affinity using directed evolution platform or structure-based rational design. We demonstrated UNC-6/netrin form large, stable, rigid complex heparin, exclude UNC-40/DCC from binding large extent. Caenorhabditis elegans with heparin-binding–deficient fail establish proper gonad morphology due abrogated which relies signaling response UNC-6. Combining mutations targeting contacts complete migration guidance defects. Our findings netrin be mediated through glycosaminoglycan-regulated macromolecular complex.

Язык: Английский

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Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses

Journal of Neuroscience, Год журнала: 2024, Номер 44(23), С. e1978232024 - e1978232024

Опубликована: Апрель 29, 2024

Latrophilin-1 (Lphn1, aka CIRL1 and CL1; gene symbol

Язык: Английский

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A universal residue numbering scheme for the Immunoglobulin-fold (Ig-fold) to study Ig-Proteomes and Ig-Interactomes

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 11, 2024

ABSTRACT The Immunoglobulin fold (Ig-fold) is found in proteins from all domains of life and represents the most populous human genome, with current estimates ranging 2 to 3% protein coding regions. That proportion much higher surfaceome where Ig Ig-like orchestrate cell-cell recognition, adhesion signaling. ability Ig-domains reliably self-assemble through highly specific interfaces a remarkable property these domains, making them key elements molecular interaction systems: immune system, nervous vascular system muscular system. We define universal residue numbering scheme, common sharing Ig-fold order study wide spectrum Ig-domain variants constituting Ig-proteome Ig-Ig interactomes at heart systems . “IgStrand scheme” enables identification structural proteomes between any species, comparative structural, functional, evolutionary analyses. review how are classified today as topological highlight “Ig-fold irreducible signature” shared by them. IgStrand scheme lays foundation for systematic annotation detecting accurately labeling Ig-, Ig-extended proteins, which poorly annotated databases opens door accurate machine learning. Importantly, it sheds light on robust folding algorithm used nature form beta sandwich supersecondary structures. powers an implemented interactive analysis software iCn3D systematically recognize Ig-domains, annotate perform detailed analyses comparing domain sequence, topology structure, regardless their diverse topologies or origin. provides detection mechanism that reveals unsuspected homologies among structures beyond currently identified Ig- variants. Indeed, multiple folds independently contain signature, particular jelly-rolls. Examples harbor “Ig-extended” architecture given. Applications engineering around Ig-architecture straightforward based numbering. AUTHOR SUMMARY conserved has diversified extensively throughout evolution provide significant number types variable forms. Primarily known its role vertebrate presence structure antibodies, myriad involved biological/structural functions within immune, nervous, vascular, systems, they mediate neural development, cell Structurally, consists 70-110 amino acids two sheets stabilized hydrogen bonds facing each other configuration. This stability tremendous adaptability, fundamental building block many families across bacteria vertebrates. abundant accounting least 2-3% protein-coding regions, underestimate no reliable method exists date can identify precision. To better importantly interactions behind biological functions, was developed. It down level interactions, allowing deconstruction variant tertiary quaternary will assist rational design scratch Ig-based therapeutics single-domain antibodies cellular therapies against antigen interest.

Язык: Английский

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Decoding the Nectin Interactome: Implications for Brain Development, Plasticity, and Neurological Disorders

ACS Chemical Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Март 2, 2025

The nectin family of cell adhesion molecules (CAMs) comprising nectins and nectin-like has emerged as a key regulator various pivotal neural processes, including neuronal development, migration, synapse formation, plasticity. Nectins engage in homophilic heterophilic interactions to mediate cell-cell adhesion, contributing the establishment maintenance circuits. Their extracellular domains facilitate trans-synaptic interactions, while intracellular participate signaling cascades influencing cytoskeletal dynamics synaptic function. exhibition distinct localization patterns neurons, astrocytes, blood-brain barrier underscores their diverse roles brain. dysregulation been implicated several neurological disorders, such neurodevelopmental depression, schizophrenia, Alzheimer's disease. This review examines structural functional characteristics distribution molecular mechanisms governing connectivity cognition. It further discusses experimental studies unraveling nectin-mediated pathophysiology potential therapeutic interventions targeting nectin-related pathways. Collectively, this comprehensive analysis highlights significance brain function, paving way for future research directions clinical implications.

Язык: Английский

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Expanding ligand-receptor interaction networks for axon guidance: Structural insights into signal crosstalk and specificity

Current Opinion in Neurobiology, Год журнала: 2025, Номер 92, С. 102999 - 102999

Опубликована: Март 20, 2025

Guidance of nascent axons to their targets is mediated by attractive and repulsive cues that activate receptors on the axonal growth cone. The number ligand-receptor interactions implicated in axon pathfinding still expanding, large-scale cell-surface extracellular protein interactome studies have revealed extensive crosstalk between signaling axes once thought act independently. This raises question how apparent promiscuity molecular compatible with specific outcomes effects cone steering. Structural provided insights into modularity binding shown capacity engage multiple ligands. Here, we review recent findings about complexity interaction networks for guidance, structures complexes reveal mechanisms may specify output.

Язык: Английский

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IgStrand: A universal residue numbering scheme for the immunoglobulin-fold (Ig-fold) to study Ig-proteomes and Ig-interactomes

PLoS Computational Biology, Год журнала: 2025, Номер 21(4), С. e1012813 - e1012813

Опубликована: Апрель 14, 2025

The Immunoglobulin fold (Ig-fold) is found in proteins from all domains of life and represents the most populous human genome, with current estimates ranging 2 to 3% protein coding regions. That proportion much higher surfaceome where Ig Ig-like orchestrate cell-cell recognition, adhesion signaling. ability Ig-domains reliably self-assemble through highly specific interfaces a remarkable property these domains, making them key elements molecular interaction systems: immune system, nervous vascular system muscular system. We define universal residue numbering scheme, common sharing Ig-fold order study wide spectrum Ig-domain variants constituting Ig-proteome Ig-Ig interactomes at heart systems . “IgStrand scheme” enables identification structural proteomes between any species, comparative structural, functional, evolutionary analyses. review how are classified today as topological highlight “Ig-fold irreducible signature” shared by them. IgStrand scheme lays foundation for systematic annotation detecting accurately labeling Ig-, Ig-extended proteins, which poorly annotated databases opens door accurate machine learning. Importantly, it sheds light on robust folding algorithm used nature form beta sandwich supersecondary structures. powers an implemented interactive analysis software iCn3D systematically recognize Ig-domains, annotate perform detailed analyses comparing domain sequence, topology structure, regardless their diverse topologies or origin. provides detection mechanism that reveals unsuspected homologies among structures beyond currently identified Ig- variants. Indeed, multiple folds independently contain signature, particular jelly-rolls. Examples harbor “Ig-extended” architecture given. Applications engineering around Ig-architecture straightforward based numbering.

Язык: Английский

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