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71.
The adapter protein Fe65 has been proposed to be the link between the intracellular domains of the amyloid precursor protein, APP (AICD), and the low-density lipoprotein receptor-related protein (LRP-CT). Functional linkage between these two proteins has been established, and mutations within LRP-CT affect the amount of Aβ produced from APP. Previous work showed that AICD binds to protein interaction domain 2 (PID2) of Fe65. Although the structure of PID1 was determined recently, all attempts to demonstrate LRP-CT binding to this domain failed. We used biophysical experiments and binding studies to investigate the binding among these three proteins. Full-length Fe65 bound more weakly to AICD than did N-terminally truncated forms; however, the intramolecular domain-domain interactions that had been proposed to inhibit binding could not be observed using amide H-D exchange. Surprisingly, when LRP-CT is phosphorylated at Tyr4507, it bound to Fe65 PID1 despite the fact that this domain belongs to the Dab-like subclass of PIDs that are not supposed to be phosphorylation-dependent. Mutation of a critical arginine abolished binding, providing further proof of the phosphorylation dependence. Fe65 PID1 thus provides a link between the Dab-like class and the IRS-like class of PIDs and is the first Dab-like family member to show phosphorylation-dependent binding. 相似文献
72.
Xu Q Axelrod HL Abresch EC Paddock ML Okamura MY Feher G 《Structure (London, England : 1993)》2004,12(4):703-715
In the photosynthetic reaction center (RC) from Rhodobacter sphaeroides, the reduction of a bound quinone molecule Q(B) is coupled with proton uptake. When Asp-L213 is replaced by Asn, proton transfer is inhibited. Proton transfer was restored by two second-site revertant mutations, Arg-M233-->Cys and Arg-H177-->His. Kinetic effects of Cd(2+) on proton transfer showed that the entry point in revertant RCs to be the same as in the native RC. The structures of the parental and two revertant RCs were determined at resolutions of 2.10, 1.80, and 2.75 A. From the structures, we were able to delineate alternate proton transfer pathways in the revertants. The main changes occur near Glu-H173, which allow it to substitute for the missing Asp-L213. The electrostatic changes near Glu-H173 cause it to be a good proton donor and acceptor, and the structural changes create a cavity which accommodates water molecules that connect Glu-H173 to other proton transfer components. 相似文献
73.
The fibroblast growth factor receptor (FGFR) substrate 2 (FRS2) family proteins function as scaffolding adapters for receptor tyrosine kinases (RTKs). The FRS2α proteins interact with RTKs through the phosphotyrosine‐binding (PTB) domain and transfer signals from the activated receptors to downstream effector proteins. Here, we report the nuclear magnetic resonance structure of the FRS2α PTB domain bound to phosphorylated TrkB. The structure reveals that the FRS2α‐PTB domain is comprised of two distinct but adjacent pockets for its mutually exclusive interaction with either nonphosphorylated juxtamembrane region of the FGFR, or tyrosine phosphorylated peptides TrkA and TrkB. The new structural insights suggest rational design of selective small molecules through targeting of the two conjunct pockets in the FRS2α PTB domain. Proteins 2014; 82:1534–1541. © 2014 Wiley Periodicals, Inc. 相似文献
74.
Markus M. Heimesaat Ildiko R. Dunay Silvia Schulze André Fischer Ursula Grundmann Marie Alutis Anja A. Kühl Andrea Tamas Gabor Toth Miklos P. Dunay Ulf B. G?bel Dora Reglodi Stefan Bereswill 《PloS one》2014,9(9)
Background
The neuropeptide Pituitary adenylate cyclase-activating polypeptide (PACAP) plays pivotal roles in immunity and inflammation. So far, potential immune-modulatory properties of PACAP have not been investigated in experimental ileitis.Methodology/Principal Findings
Mice were perorally infected with Toxoplasma (T.) gondii to induce acute ileitis (day 0) and treated daily with synthetic PACAP38 from day 1 to 6 post infection (p.i.; prophylaxis) or from day 4 to 6 p.i. (therapy). Whereas placebo-treated control mice suffered from acute ileitis at day 7 p.i. and succumbed to infection, intestinal immunopathology was ameliorated following PACAP prophylaxis. PACAP-treated mice exhibited increased abundance of small intestinal FOXP3+ cells, but lower numbers of ileal T lymphocytes, neutrophils, monocytes and macrophages, which was accompanied by less ileal expression of pro-inflammatory cytokines such as IL-23p19, IL-22, IFN-γ, and MCP-1. Furthermore, PACAP-treated mice displayed higher anti-inflammatory IL-4 concentrations in mesenteric lymph nodes and liver and higher systemic anti-inflammatory IL-10 levels in spleen and serum as compared to control animals at day 7 p.i. Remarkably, PACAP-mediated anti-inflammatory effects could also be observed in extra-intestinal compartments as indicated by reduced pro-inflammatory mediator levels in spleen (TNF-α, nitric oxide) and liver (TNF-α, IFN-γ, MCP-1, IL-6) and less severe histopathological sequelae in lungs and kidneys following prophylactic PACAP treatment. Strikingly, PACAP prolonged survival of T. gondii infected mice in a time-of-treatment dependent manner.Conclusion/Significance
Synthetic PACAP ameliorates acute small intestinal inflammation and extra-intestinal sequelae by down-regulating Th1-type immunopathology, reducing oxidative stress and up-regulating anti-inflammatory cytokine responses. These findings provide novel potential treatment options of inflammatory bowel diseases. 相似文献75.
The determinants of steady-state calcium loading by sarcoplasmic reticulum vesicles were evaluated by measuring the contribution of different pathways of calcium flux to the total calcium flux at steady state. The diffusional passive pathway was least significant at all calcium loads studied. Diffusional passive calcium flux was evaluated by a number of methods which gave comparable results and support its designation as passive and diffusional. These methods included (a) flux measurements with the simple pump-leak system which pertains when acetyl phosphate is used to load the vesicles; (b) flux measurements made after quenching the pump with EGTA; (c) flux measurements made after quenching the pump with glucose plus hexokinase; and (d) evaluation of the effect of pump activity on the efflux of mannitol. The calcium efflux not accounted for by the diffusional pathway was assigned to non-diffusional pathways. Efflux through the non-diffusional pathways required ATP, ADP and extravesicular Ca2+. The ADP-dependent, phosphoenzyme-independent pathway described by Beirao and DeMeis (Biochim. Biophys. Acta (1976) 433, 520-530) was not significantly involved in efflux. We propose that the level of calcium loading achieved at steady state is determined by the levels of the intermediates of the calcium pump which are established at this pseudo-equilibrium condition, these levels being determined by the concentrations of intravesicular and extravesicular calcium ([Ca2+]i and [Ca2+]), ATP and ADP. The different levels of calcium loading achieved by skeletal and cardiac sarcoplasmic reticulum are attributed to different nucleotide and calcium kinetics in these two types of sarcoplasmic reticulum and possibly to different intravesicular volumes. Differences in diffusional permeability are not responsible for differences in calcium loading. 相似文献
76.
The location of the cytochrome binding site on the reaction center of Rhodopseudomonas sphaeroides was studied by two different approaches. In one, cross-linking agents, principally dithiobis(propionimidate) and dimethyl suberimidate, were used to link cytochrome c and cytochrome c2 to reaction centers; in the other, the inhibition of electron transfer by antibodies against the subunits was investigated. Cytochrome c (horse) cross-linked to the L and M subunits, whereas cytochrome c2 (R. sphaeroides) cross-linked only to the L subunit. The cross-linked reaction center-cytochrome complexes were isolated by affinity chromatography. The rate of electron transfer in the cross-linked cytochrome c2 complex was the same as that in the un-cross-linked complex. However, when cytochrome c was used, the rate in the cross-linked complex was about 15 times slower than that in the un-cross-linked complex. Fab fragments of antibodies specific against the L and M subunits blocked electron transfer from both cytochrome c (horse) and cytochrome c2 (R. sphaeroides). Antibodies specific for the H subunit did not block either reaction. We conclude that the cytochrome binding site on the reaction center is close (approximately 10 A) to both the L and M subunits, possibly in a cleft between them. 相似文献
77.
Electron nuclear double resonance of semiquinones in reaction centers of Rhodopseudomonas sphaeroides 总被引:1,自引:0,他引:1
W Lubitz E C Abresch R J Debus R A Isaacson M Y Okamura G Feher 《Biochimica et biophysica acta》1985,808(3):464-469
Replacement of Fe2+ by Zn2+ in reaction centers of Rhodopseudomonas sphaeroides enabled us to perform ENDOR (electron nuclear double resonance) experiments on the anion radicals of the primary and secondary ubiquinone acceptors (QA- and QB-. Differences between the QA and QB sites, hydrogen bonding to the oxygens, interactions with the protons of the proteins and some symmetry properties of the binding sites were deduced from an analysis of the ENDOR spectra. 相似文献
78.
79.
80.
Charge recombination kinetics as a probe of protonation of the primary acceptor in photosynthetic reaction centers. 总被引:1,自引:0,他引:1
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The kinetics of the charge recombination D+QA-----DQA was used to probe the protonation of the primary acceptor in reaction centers from Rhodopseudomonas sphaeroides, in which the native ubiquinone was replaced by anthraquinone. We found that QA- is stabilized by the rapid (t less than 10(-2) s) binding of a proton, with a pK of 9.8. The distance between QA- and the proton binding site was estimated to be larger than approximately 5 A. 相似文献