The S100A4 protein belongs to the S100 family of vertebrate-specific proteins possessing both intra- and extracellular functions. In nervous system, high levels expression are observed at sites neurogenesis lesions, suggesting a role in neuronal plasticity. Extracellular oligomeric is potent promoter neurite outgrowth survival from cultured primary neurons; however, molecular mechanism this effect has not been established. Here we demonstrate that increases intracellular calcium...

The function of S100A4, a member the calcium-binding S100 protein family, has been associated with tumor invasion and metastasis. Although an essential pro-metastatic role extracellular S100A4 in progression demonstrated, identification precise underlying mechanisms partners (receptors) remained elusive. To identify putative targets for we screened phage display peptide library using as bait. We identified three independent motifs varying affinities protein. Sequence analyses indicated that...

There is a need for novel strategies to treat aggressive breast cancer subtypes and overcome drug resistance.

Molecular mobility in neuronal plasma membranes is a crucial factor brain function. Microscopic viscosity an important parameter that determines molecular mobility. This study presents the first direct measurement of microviscosity live neurons. Microviscosity maps were obtained using fluorescence lifetime imaging environment-sensing dyes termed "molecular rotors". Neurons investigated both basal state and following common neurodegenerative stimuli, excitotoxicity, or oxidative stress. Both...

NCAM plays a key role in neural development and plasticity-mediating cell adhesion differentiation mainly through homophilic binding. Until recently, attempts to modulate neuronal plasticity have been impeded by the absence of small synthetic agonists mimicking interactions NCAM. We show here that peptide, P2, corresponding 12-amino acid sequence localized FG loop second Ig module NCAM, binds first module, which is natural binding partner with an apparent K d 4.7 ± 0.9 × 10−6m. P2 inhibits...

Abstract The neural cell adhesion molecule (NCAM), and the growth‐associated protein (GAP‐43), play pivotal roles in neuronal development plasticity possess interdependent functions. However, mechanisms underlying functional association of GAP‐43 NCAM have not been elucidated. In this study we show that (over)expression PC12E2 cells hippocampal neurons strongly potentiates neurite extension, both absence presence homophilic binding. This potentiation is crucially dependent on membrane...

The neural cell adhesion molecule (NCAM) plays a pivotal role in the development of nervous system, promoting neuronal differentiation via homophilic (NCAM-NCAM) as well heterophilic (NCAM-fibroblast growth factor receptor [FGFR]) interactions. NCAM-induced intracellular signaling has been shown to affect and be dependent on cytoplasmic Ca2+ concentration ([Ca2+]i). However, molecular basis this remains unclear. In study, we determined [Ca2+]i regulating mechanisms involved induced by NCAM....

Erythropoietin, a member of the type 1 cytokine superfamily, controls proliferation and differentiation erythroid progenitor cells through binding to dimerization erythropoietin receptor. Both its receptor are also expressed in central nervous system, where they involved tissue protection. However, use as neuroprotective agent may be hampered by erythropoietic activity. Therefore, developing non-haematopoietic mimetics is important. Based on crystal structure complex receptor, we designed...

Understanding the mechanisms of neurodegeneration is crucial for development therapies to treat neurological disorders.S100 proteins are extensively expressed in injured brain but S100's role and signalling neural cells remain elusive.We recently demonstrated that S100A4 protein protects neurons injury designed S100A4-derived peptides mimicking its beneficial effects.Here we show neuroprotection by involves growth factor family receptor ErbB4 ligand Neuregulin 1 (NRG), key regulators...

Amyloid deposits of aggregated beta-amyloid Aβ(1-42) peptides are a pathological hallmark Alzheimer's disease. aggregates known to induce biophysical alterations in cells, including disruption plasma membranes. We investigated the microviscosity membranes upon interaction with oligomeric and fibrillar forms Aβ(1-42). Viscosity-sensing fluorophores termed molecular rotors were utilised directly measure microviscosities giant membrane vesicles (GPMVs) live SH-SY5Y HeLa cells. The fluorescence...

Directly and accurately characterizing the transport of nanoparticles across blood–brain barrier will greatly advance delivery therapies against brain disorders.

The neural cell adhesion molecule (NCAM) plays a key role in morphogenesis of the nervous system and remodeling neuronal connections accompanying regenerative cognitive processes. Recently, new synthetic ligand NCAM, C3-peptide, which binds to NCAM IgI module, has been identified by means combinatorial chemistry (Rønn, L. C. B, Olsen, M., Ostergaard, S., Kiselyov, V., Berezin, Mortensen, M. T., Lerche, H., Jensen, P. Soroka, Saffell, J. L., Doherty, P., Poulsen, F. Bock, E., Holm, A.,...

Neuroplastin (Np) is a glycoprotein belonging to the immunoglobulin superfamily of cell adhesion molecules (CAMs) and existing in two isoforms, Np55 Np65, named according their molecular weights. The extracellular part Np65 contains three (Ig)-like modules (Igl, Ig2, Ig3), whereas lacks Igl module. Of these only involved homophilic interactions resulting adhesion, role poorlyunderstood. present studyreports for first time crystal structure ectodomain at 1.95-Å resolution demonstrates that...

Neuroplastin-65 (Np65) is a brain-specific cell adhesion molecule belonging to the immunoglobulin superfamily. Homophilic trans-interaction of Np65 mediates between cells and modulates synaptic plasticity. This interaction solely occurs through first (Ig) module Np65, but exact binding mechanism has not yet been elucidated. In this study, we identify homophilic motif show that synthetic peptide modeled after motif, termed enplastin, binds Np65. We demonstrate both Np65- enplastin-induced...

A challenge in neurology is the lack of efficient brain-penetrable neuroprotectants targeting multiple disease mechanisms. Plasmonic gold nanostars are promising candidates to deliver standard-of-care drugs inside brain but have not been trialed as carriers for neuroprotectants. Here, we conjugated custom-made peptide dendrimers (termed H3/H6), encompassing motifs neurotrophic S100A4-protein, onto star-shaped and spherical nanostructures (H3/H6-AuNS/AuNP) evaluated their potential...

Abstract The ability to image cell chemistry at the nanoscale is key for understanding biology, but many optical microscopies are restricted by ~(200–250)nm diffraction limit. Electron microscopy and super-resolution fluorescence techniques beat this limit, rely on staining specialised labelling generate contrast. It challenging, therefore, obtain information about functional of intracellular components. Here we demonstrate a technique label-free chemical mapping with (~30 nm) resolution. We...

Apart from its hematopoietic activity, erythropoietin (EPO) is also known as a tissue-protective cytokine. In the brain, EPO and receptor are up-regulated in response to insult exert pro-survival effects. binds (EPOR) via high- low-affinity binding sites (Sites 1 2, respectively), inducing conformational changes receptor, followed by activation of downstream signaling cascades. Based on crystal structure EPO:EPOR(2) complex, we designed peptide, termed Epobis, whose sequence encompassed...

Abstract We recently found that S100A4, a member of the multifunctional S100 protein family, protects neurons in injured brain and identified two sequence motifs S100A4 mediating its neurotrophic effect. Synthetic peptides encompassing these stimulated neuritogenesis survival vitro mimicked S100A4-induced neuroprotection trauma. Here, we investigated possible function mimetics pathologies peripheral nervous system (PNS). was expressed PNS peptide mimetic (H3) affected regeneration myelinated...

Abstract Metallothioneins I and II (MTI/II) are metal‐binding proteins overexpressed in response to brain injury. Recently, we have designed a peptide, termed EmtinB, which is modeled after the β‐domain of MT‐II mimics biological effects MTI/II vitro. Here, demonstrate neuroprotective effect EmtinB vitro vivo models kainic acid (KA)‐induced neurotoxicity. We show that passes blood–brain barrier detectable plasma for up 24 hr. Treatment with significantly attenuates seizures C57BL/6J mice...

Cell adhesion molecules (CAMs) play a pivotal role in the development and maintenance of nervous system under normal conditions. They also are involved numerous pathological processes such as inflammation, degenerative disorders, cancer, making them attractive targets for drug development. The majority CAMs signal transducing receptors. CAM-induced intracellular signalling is triggered via homophilic (CAM-CAM) heterophilic (CAM - other counter-receptors) interactions, which both can be...

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate controlling fundamental physiological processes in the central nervous system, such as learning and memory. Excessive activation of NMDARs causes excitotoxicity results neurodegeneration, which is observed a number pathological conditions. Because their dichotomous role, therapeutic targeting NMDAR difficult. However, several lines evidence suggest that predominantly linked to extrasynaptically located NMDARs. Here, we report...

Abstract The ability to image cell chemistry at the nanoscale is key for understanding biology, but many optical microscopies are restricted by ~250nm diffraction limit. Electron microscopy and super-resolution fluorescence techniques beat this limit, rely on staining specialised labelling generate contrast. It challenging, therefore, obtain information about functional of intracellular components. Here we demonstrate a technique label-free chemical mapping with (~30nm) resolution. We use...