The neurovascular unit is an emerging concept that emphasizes homeostatic interactions between endothelium and cerebral parenchyma. Here, we show are not just inert tubes for delivering blood, but they also secrete trophic factors can be directly neuroprotective. Conditioned media from endothelial cells broadly protects neurons against oxygen-glucose deprivation, oxidative damage, endoplasmic reticulum stress, hypoxia, amyloid neurotoxicity. This phenomenon largely mediated by...

Conformational communication across the plasma membrane between extracellular and intracellular domains of integrins is beginning to be defined by structural work on both domains. However, role alpha beta subunit transmembrane nature signal transmission through these have been elusive. Disulfide bond scanning exofacial portions integrin alpha(IIbeta) beta(3) reveals a specific heterodimerization interface in resting receptor. This lost rather than rearranged upon activation receptor...

Residues important in the interaction between 23-residue transmembrane (TM) domains of integrin alpha(IIb)- and beta(3)-subunits were identified by mutating each non-Leu residue to Leu. Leu substitutions alpha(IIb) at G972, G976, T981, beta(3) I693 G708, increased ligand binding. Substitutions with other amino acids alpha(IIb)G972 beta(3)G708 could also increase The results are consistent extend helical interface alpha- beta-subunit TM previously defined cysteine scanning disulfide bond...

The affinity of the extracellular domain integrins for ligand is regulated by conformational changes signaled from cytoplasm. Alternative types movement in ligand-binding headpiece have been proposed. In one study, electron micrograph image averages integrin aVβ3 show two different conformations. open conformation present when a mimetic peptide bound and differs closed presence an obtuse angle between β3 subunit hybrid I-like domains. We tested hypothesis that opening hybrid-I-like interface...

The TAN-1 gene was originally discovered at the breakpoint of a recurrent (7;9)(q34;q34.3) chromosomal translocation found in subset human T-lymphoblastic leukemias (Reynolds et al. 1987; Smith 1988; Ellisen 1991). This joins roughly 3′ half head-to-head with portion β T-cell-receptor (TCRB) beginning 5′ boundary one or other J segment. Intact is normally transcribed into an 8.2-kb transcript that present many tissues, most abundantly developing thymus and spleen (Ellisen tissue distribution...

Many questions about the significance of structural features integrin α(V)β(3) with respect to its mechanism activation remain. We have determined and re-refined crystal structures ectodomain linked C-terminal coiled coils (α(V)β(3)-AB) four transmembrane (TM) residues in each subunit (α(V)β(3)-1TM), respectively. The α(V) β(3) subunits eight extracellular domains, respectively, are bent at knees between headpiece lower legs, has closed, low-affinity conformation. differ occupancy three...

The ligand binding function of integrins can be modulated by various monoclonal antibodies both direct and indirect mechanisms. We have characterized an anti-β1 antibody, SG/19, that had been reported to inhibit the β1 integrin on cell surface. SG/19 recognized wild type subunit exists in a conformational equilibrium between high low affinity states but bound poorly mutant locked state. Epitope mapping revealed Thr82 subunit, located at outer face boundary I-like hybrid domains, was key...

Despite extensive evidence that integrin conformational changes between bent and extended conformations regulate affinity for ligands, an alternative hypothesis has been proposed in which a "deadbolt" can ligand the absence of extension. Here, we tested both deadbolt extension models. According to model, hairpin loop β3 tail domain could act as restrain displacement I β6-α7 maintain low state. We found mutating or deleting no effect on binding by either αIIbβ 3 αVβ3 integrins. In contrast,...

We examined the effect of conformational change at beta(7) I-like/hybrid domain interface on regulating transition between rolling and firm adhesion by integrin alpha(4)beta(7). An N-glycosylation site was introduced into to act as a wedge stabilize open conformation this hence alpha(4) headpiece. Wild-type alpha(4)beta(7) mediates in Ca(2+) Ca(2+)/Mg(2+) but Mg(2+) Mn(2+). Stabilizing headpiece resulted all divalent cations. The interaction metal binding sites I-like with hybrid double...

Non-ionic water-soluble helical polypeptides bearing reactive side chains can be efficiently modified with hydrophobic or hydrophilic moieties to produce conjugates.

On the basis of sequence homology studies, it has been suggested that association human erythrocytes alpha and beta spectrin at tetramerization site involves interactions between helices. However, no empirical details are available, presumably due to experimental difficulties in studying molecules because its size and/or structural flexibility. It speculated erythrocyte helical bundling rather than coiled coil association. We have used recombinant peptides model study their site. Two...

Integrin transmembrane (TM) and/or cytoplasmic domains play a critical role in integrin bidirectional signaling. Although it has been shown that TM α and β associate the resting state separation of these is required for both inside-out outside-in signaling, homomeric association remains elusive. Formation homo-oligomers was observed micelles bacterial membranes previously, proposed important activation clustering. This study addresses whether form mammalian cell using cysteine scanning...

The ability of αIIbβ3 to bind ligands and undergo outside-in signaling is regulated by three divalent cation binding sites in the β I domain. Specifically, metal ion-dependent adhesion site (MIDAS) synergistic (SyMBS) are thought be required for ligand due their synergy between Ca(2+) Mg(2+). adjacent MIDAS (ADMIDAS) an important regulatory that also acts as a critical link hybrid domains signaling. Mutations this have provided conflicting results different integrins. We mutated β3 SyMBS...

Antifreeze proteins (AFPs) enhance the survival of organisms inhabiting cold environments by affecting formation and/or structure ice. We report crystal first multi-domain AFP that has been characterized. The two ice binding domains are structurally similar. Each consists an irregular β-helix with a triangular cross-section and long α-helix runs parallel on one side β-helix. Both stabilized hydrophobic interactions. A flat plane same face each domain's was identified as site. Mutating any...

Integrin conformational changes mediate integrin activation and signaling triggered by intracellular molecules or extracellular ligands. Even though it is known that αβ transmembrane domain separation required for signaling, still not clear how this signal transmitted from the through two long legs to ligand-binding headpiece. This study addresses whether of membrane-proximal critical outside-in signaling. Using a disulfide bond restrict dissociation α-subunit Calf-2 β-subunit I-EGF4 domain,...

Liquid water present in polycrystalline ice at the interstices between crystals results a network of liquid-filled veins and nodes within solid matrix, making low porosity porous media. Here we used nuclear magnetic resonance (NMR) relaxation time dependent self-diffusion measurements developed for media applications to monitor three dimensional changes vein ices with without bacterial binding protein (IBP). Shorter effective diffusion distances were detected as function increased...