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31.
Receptor-like protein tyrosine phosphatases (RPTPs) are type I integral membrane proteins. Together with protein tyrosine kinases, RPTPs regulate the phosphotyrosine levels in the cell. Studies of two RPTPs, CD45 and PTPalpha, have provided strong evidence that dimerization leads to inactivation of the receptors, and that the dimerization of PTPalpha involves interactions in the transmembrane domain (TMD). Using the TOXCAT assay, a genetic approach for analyzing TM interactions in Escherichia coli membranes, we show that the TMD of RPTPs interact in the membrane, albeit to different extents. Using fusion proteins of TMDs, we also observe an equilibrium between monomer and dimer in sodium dodecyl sulfate (SDS) micelles. Through a mutational study of the DEP1 TMD, we demonstrate that these interactions are specific. Taken together, our results define a subset of the RPTP family in which TM homodimerization may act as a mediator of protein function. 相似文献
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Hao Wang Kellie A. Jurado Xiaolin Wu Ming-Chieh Shun Xiang Li Andrea L. Ferris Steven J. Smith Pratiq A. Patel James R. Fuchs Peter Cherepanov Mamuka Kvaratskhelia Stephen H. Hughes Alan Engelman 《Nucleic acids research》2012,40(22):11518-11530
The binding of integrase (IN) to lens epithelium-derived growth factor (LEDGF)/p75 in large part determines the efficiency and specificity of HIV-1 integration. However, a significant residual preference for integration into active genes persists in Psip1 (the gene that encodes for LEDGF/p75) knockout (KO) cells. One other cellular protein, HRP2, harbors both the PWWP and IN-binding domains that are important for LEDGF/p75 co-factor function. To assess the role of HRP2 in HIV-1 integration, cells generated from Hdgfrp2 (the gene that encodes for HRP2) and Psip1/Hdgfrp2 KO mice were infected alongside matched control cells. HRP2 depleted cells supported normal infection, while disruption of Hdgfrp2 in Psip1 KO cells yielded additional defects in the efficiency and specificity of integration. These deficits were largely restored by ectopic expression of either LEDGF/p75 or HRP2. The double-KO cells nevertheless supported residual integration into genes, indicating that IN and/or other host factors contribute to integration specificity in the absence of LEDGF/p75 and HRP2. Psip1 KO significantly increased the potency of an allosteric inhibitor that binds the LEDGF/p75 binding site on IN, a result that was not significantly altered by Hdgfrp2 disruption. These findings help to rule out the host factor-IN interactions as the primary antiviral targets of LEDGF/p75-binding site IN inhibitors. 相似文献
34.
Selective tyrosine kinase inhibitors have emerged as important therapeutic agents in the treatment of a variety of human malignancies. Although several of these inhibitors have marked clinical activity, it is widely recognized that the overall value of these agents is substantially limited by the acquisition of drug resistance, which eventually arises in most, if not all treated patients. Mechanisms of drug resistance are beginning to be elucidated through the molecular analysis of clinical specimens as well as through cell culture modeling. By identifying resistance mechanisms, it should be possible to develop 'second-generation' inhibitors as well as rational drug combinations that can overcome or even prevent acquired resistance to kinase inhibitors, thereby enhancing clinical benefit. 相似文献
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This paper describes experimental tests of the hypothesis that bacteriorhodopsin (BR) can fold by the association of independently stable transmembrane helices. Peptides containing the first and second helical segments of BR were chemically synthesized. These two peptides and the complementary five-helix fragment of BR were reconstituted in three separate populations of native-lipid vesicles which were then mixed and fused to allow the fragments to interact. After addition of retinal, absorption spectroscopy of the reconstituted BR and X-ray diffraction of two-dimensional crystals of this material showed that the native structure of BR was regenerated. The first two helices of BR can therefore be considered as independent folding domains, and covalent connections in the loops connecting the helices to each other and to the rest of the molecule are not essential for the appropriate association of the helices. 相似文献
37.
Localization of two chymotryptic fragments in the structure of renatured bacteriorhodopsin by neutron diffraction. 总被引:4,自引:2,他引:2 下载免费PDF全文
The structure of crystalline purple membrane reconstituted from purified bacteriorhodopsin (BR) chymotryptic fragments has been studied by neutron diffraction. In one of the samples studied, the fragment C-2, encompassing the first two predicted transmembrane segments, was prepared from deuterated purple membrane. The diffraction changes when the natural C-2 fragment is substituted by a deuterated one are analysed in terms of a seven-helix model for BR. The assignment of the labelled fragment to one end of the molecule placed new constraints on folding models for the protein. 相似文献
38.
Cannabinoids purportedly improve taste responsiveness and enhancethe sensory appeal of foods. These properties and a commonlycited oral drying effect were evaluated in a series of studieswith light marijuana users. The first was a double-blind,placebo-controlled, acute oral dosing trial, involving an ageand gender stratified sample of 57 adults. An influence of routeof drug delivery was explored in another 11 individuals whowere administered a single dose orally, sublingually and viacigarette. To explore effects following chronic administration,six additional individuals were dosed twice per day for 3 daysorally and by rectal suppository. Taste intensity and hedonicresponses for sweet, sour, salty and bitter food stimuli weremonitored at baseline, 2, 4 and 6 hours post-dosing in the acutestudies, and daily in the chronic study. Stimulated saliva sampleswere collected at these same times. Salivary flow rate was significantlynegatively correlated with plasma drug levels, and reportedhigh 2 and 4 h post-dosing. No effects of thedrug were observed on taste responses. Self-reported shiftsin taste responsiveness and hedonics may be related to alterationsof memory and cognition, rather than gustatory function. 相似文献
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J A Engelman X L Zhang B Razani R G Pestell M P Lisanti 《The Journal of biological chemistry》1999,274(45):32333-32341