Fibulin‐4 and latent‐transforming growth factor beta‐binding protein‐4 interactions with syndecan‐2 and syndecan‐3 are required for elastogenesis

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(7)

Published: April 1, 2025

Abstract Elastogenesis is a cell surface‐located hierarchical process that requires the core components tropoelastin and fibrillins several accessory proteins, including fibulin‐4 (FBLN4) latent TGF‐β binding protein‐4 (LTBP4). FBLN4 LTBP4 interact with cells, but their receptors associated molecular elastogenic mechanisms remain unknown. Primary skin fibroblasts vascular smooth muscle cells bound strongly to multimers monomers. We identified two interaction epitopes on located in cbEGF2‐3 C‐terminal domain, whereas multimerization sites were mapped cbEGF4‐5 domain. also determined novel site N‐terminal half of LTBP4. Cell was inhibited presence heparin, heparan sulfate, or after enzymatic removal suggesting sulfate proteoglycans as relevant surface receptors. siRNA knockdown experiments syndecan (SDC)2 SDC3 for FBNL4 Direct protein interactions between recombinant ectodomains SDC2 SDC3, validated these results. Interaction enhanced elastogenesis, and/or knockdowns led reduced elastic fiber formation. The significantly focal adhesion formation, induced contraction, activation kinase (FAK), Erk1/2, RhoA. Pharmacological inhibition effectors markedly attenuated levels pFAK, pERK, active Together, data demonstrate through promote elastogenesis by enhancing leading contractility FAK, RhoA activation, underscoring significance pathways elastogenesis.

Language: Английский

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The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(18), P. 14101 - 14101

Published: Sept. 14, 2023

This review examines the roles of HS-proteoglycans (HS-PGs) in general, and, particular, perlecan and syndecan as representative examples their interactive ligands, which regulate physiological processes cellular behavior health disease. HS-PGs are essential for functional properties tissues both development extracellular matrix (ECM) remodeling that occurs response to trauma or interact with a biodiverse range chemokines, chemokine receptors, protease inhibitors, growth factors immune regulation, inflammation, ECM stabilization, tissue protection. Some cell regulatory proteoglycan receptors dually modified hybrid HS/CS proteoglycans (betaglycan, CD47). Neurexins provide synaptic plasticity, specificity interaction, promoting neurotransduction, neurogenesis, differentiation. Ternary complexes glypican-1 Robbo-Slit neuroregulatory proteins direct axonogenesis neural network formation. Specific neurexin-neuroligin stabilize interactions activity. Disruption these leads neurological deficits disorders cognitive decline. Interactions also promote inhibit tumor development. Thus, have complex diverse normal pathological tissues. Specialized HS-PGs, such neurexins, pikachurin, Eyes-shut, stabilization transduction axenome primary cilium phototoreceptors ribbon synapse bipolar neurons retinal networks, ocular vision. Pikachurin Eyes-Shut an α-dystroglycan photoreceptor synapse. Novel controlling function expected continue be uncovered this fascinating class proteoglycan.

Language: Английский

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How AlphaFold2 shaped the structural coverage of the human transmembrane proteome

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Nov. 20, 2023

AlphaFold2 (AF2) provides a 3D structure for every known or predicted protein, opening up new prospects virtually field in structural biology. However, working with transmembrane protein molecules pose notorious challenge scientists, resulting limited number of experimentally determined structures. Consequently, algorithms trained on this finite training set also face difficulties. To address issue, we recently launched the TmAlphaFold database, where structures are embedded into membrane plane and quality assessment (plausibility membrane-embedded structure) is provided each prediction using geometrical evaluation. In paper, analyze how AF2 has improved coverage proteins compared to earlier years when only experimental were available, high-throughput was greatly limited. We evaluate can be used search (distant) homologs highly diverse families. By combining homology search, pinpoint families accuracy still limited, determination would desirable.

Language: Английский

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Proteoglycan Dysfunction: A Common Link Between Intervertebral Disc Degeneration and Skeletal Dysplasia

Neurospine, Journal Year: 2024, Volume and Issue: 21(1), P. 162 - 178

Published: March 28, 2024

Proteoglycans through their sulfated glycosaminoglycans regulate cell-matrix signaling during tissue development, regeneration, and degeneration processes. Large extracellular proteoglycans such as aggrecan, versican, perlecan are especially important for the structural integrity of intervertebral disc cartilage development. In these tissues, responsible hydration, joint flexibility, absorption mechanical loads. Loss or reduction molecules can lead to skeletal dysplasia, evident from loss height defects in development respectively. this review, we discuss common found elaborate on various murine models dysplasias humans highlight how absence and/or aberrant expression causes accelerated developmental defects.

Language: Английский

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Likely pathogenic variants of SDC3, KCNA2, KCNK1, KCNK16 and HSF1 are in support of acquired irreversible PIEZO2 channelopathy in ALS onset

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Amyotrophic lateral sclerosis is a multisystem progressive neurodegenerative disease. A recent theory of ALS proposed that the disease initiating primary damage an acquired irreversible intrafusal proprioceptive terminal PIEZO2 channelopathy with underlying genetic and environmental risk factors. Underpinning this these ion channels initiate ultrafast proton-based oscillatory signaling to motor neurons through VGLUT1 hippocampus VGLUT2. This may gradually degenerate in which process K_v1.2 are depleted. Furthermore, it also depletes heat shock transcription factor-1 hippocampus, hence negatively affecting adult hippocampal neurogenesis. In addition, not only PIEZO2-PIEZO2 crosstalk fully disrupted progressively between afferent terminals due lost initiated cross-coupled Huygens synchronization, but PIEZO2-PIEZO1 on periphery. Syndecans, especially syndecan-3 nervous system, critical players maintenance PIEZO crosstalk. The detected charge altering variants likely promotes impairment crosstalk, loss as well. Variants KCNA2 facilitate faster function when prevails, mention potassium current rectifying encoding KCNK1 KCNK16 propel provide autoimmune-like pathogenic background. Moreover, diminishing presence identified HSF1 variants, leading impaired

Language: Английский

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A Syndecan‐Mediated Journey

Proteoglycan Research, Journal Year: 2025, Volume and Issue: 3(1)

Published: Jan. 1, 2025

ABSTRACT A brief, personal, retrospective on my career is presented, focusing the path that led from studies fibroblast focal adhesions to signaling roles of syndecan‐4. This summary framed against backdrop major discoveries in cell adhesion field influenced our research direction, ultimately leading discovery events involve kinases, microfilament dynamics, and ion channels. Syndecan regulation stretch‐activated transient receptor potential channels appears be a property extends back invertebrates probably intrinsic their origins.

Language: Английский

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The transmembrane protein Syndecan is required for stem cell survival and maintenance of their nuclear properties

PLoS Genetics, Journal Year: 2025, Volume and Issue: 21(2), P. e1011586 - e1011586

Published: Feb. 6, 2025

Tissue maintenance is underpinned by resident stem cells whose activity modulated microenvironmental cues. Using Drosophila as a simple model to identify regulators of cell behaviour and survival in vivo , we have identified novel connections between the conserved transmembrane proteoglycan Syndecan, nuclear properties function. In midgut, Syndecan depletion intestinal results their loss from tissue, impairing tissue renewal. At cellular level, alters shape, causes lamina invaginations DNA damage. second developing brain, live imaging revealed that neural envelope remodelling defects which arise upon division. Our findings reveal new role for diverse types.

Language: Английский

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CNS/PNS proteoglycans functionalize neuronal and astrocyte niche microenvironments optimizing cellular activity by preserving membrane polarization dynamics, ionic microenvironments, ion fluxes, neuronal activation, and network neurotransductive capacity

Journal of Neuroscience Research, Journal Year: 2024, Volume and Issue: 102(7)

Published: July 1, 2024

Abstract Central and peripheral nervous system (CNS/PNS) proteoglycans (PGs) have diverse functional roles, this study examined how these control cellular behavior tissue function. The CNS/PNS extracellular matrix (ECM) is a dynamic, responsive, highly interactive, space‐filling, cell supportive, stabilizing structure maintaining compartments, ionic microenvironments, microgradients that regulate neuronal activity maintain the neuron in an optimal microenvironment. contains high glycosaminoglycan content (60% hyaluronan, HA) range of PGs. Immobilization HA brain tissues by interactive hyalectan PGs preserves hydration activity, paucity results pro‐convulsant epileptic phenotype. Diverse CS, KS, HSPGs stabilize blood–brain barrier neurovascular unit, provide smart gel neurotransmitter vesicle storage delivery, organize neuromuscular junction basement membrane, motor synaptic plasticity, photoreceptor functions. PG‐HA networks fluxes compartments contribute to membrane polarization dynamics essential activation neurotransduction. Hyalectans form neuroprotective perineuronal nets contributing memory, cognitive learning. Sialoglycoprotein associated with cones rods (SPACRCAN), binding CSPG, stabilizes inter‐photoreceptor ECM. pikachurin eyes shut synapse aiding phototransduction neurotransduction retinal bipolar neurons crucial visual acuity. This achieved through Laminin G motifs pikachurin, shut, neurexins interact dystroglycan–cytoskeleton–ECM‐stabilizing interconnections, specificity, co‐ordination regulatory action potentials neural networks.

Language: Английский

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How AlphaFold shaped the structural coverage of the human transmembrane proteome

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 18, 2023

Abstract AlphaFold2 (AF2) provides structures for every protein, opening up prospects virtually field in structural biology. However, transmembrane proteins pose a challenge experimental scientists, resulting limited number of solved structures. Consequently, algorithms trained on this finite training set also face difficulties. To address issue, we recently launched the TmAlphaFold database, where predicted are embedded into membrane and quality assessment is provided each prediction using geometrical evaluation. In paper, analyze how AF2 has changed coverage compared to earlier years when only were available, high-throughput structure was greatly limited. We evaluate can be used search (distant) homologs highly diverse protein families. By combining homology search, pinpoint families accuracy limited, approaches still desired.

Language: Английский

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Interplay of heparan sulfate chains with the core proteins of syndecans 2 and 4

Proteoglycan Research, Journal Year: 2023, Volume and Issue: 1(3)

Published: July 1, 2023

Abstract We have previously shown that the extracellular domains of four syndecans are intrinsically disordered, and adopt a wide range conformations. report here building coarse‐grained models human 2 4 using small‐angle X‐ray scattering restraints. One, two or three heparan sulfate (HS) hexadecasaccharides, (IdoA[2S]GlcNS[6S]) 8 , were attached to serine residues core proteins, resulting in eight variants for each syndecan used all‐atom molecular dynamics (MD) simulations (0.5–1 µs). Syndecan‐4 had larger conformational diversity than syndecan‐2, remained extended during MD absence HS whereas syndecan‐2 adopted more compact Their proteins thus appeared be structurally distinct. The chains also behave differently, middle chain being flexible syndecan‐4, third able interact with protein regions mediating cell adhesion. adhesion sites on both flexible, without chains, NXIP motif located particularly region. In conclusion, induce moderate changes syndecans, depending number their location protein, itself.

Language: Английский

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