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91.
Membrane targeting by APPL1 and APPL2: dynamic scaffolds that oligomerize and bind phosphoinositides
Chial HJ Wu R Ustach CV McPhail LC Mobley WC Chen YQ 《Traffic (Copenhagen, Denmark)》2008,9(2):215-229
Human adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1) and adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 2 (APPL2) are homologous effectors of the small guanosine triphosphatase RAB5 that interact with a diverse set of receptors and signaling proteins and are proposed to function in endosome-mediated signaling. Herein, we investigated the membrane-targeting properties of the APPL1 and APPL2 Bin/Amphiphysin/Rvs (BAR), pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains. Coimmunoprecipitation and yeast two-hybrid studies demonstrated that full-length APPL proteins formed homooligomers and heterooligomers and that the APPL minimal BAR domains were necessary and sufficient for mediating APPL-APPL interactions. When fused to a fluorescent protein and overexpressed, all three domains (minimal BAR, PH and PTB) were targeted to cell membranes. Furthermore, full-length APPL proteins bound to phosphoinositides, and the APPL isolated PH or PTB domains were sufficient for in vitro phosphoinositide binding. Live cell imaging showed that full-length APPL-yellow fluorescent protein (YFP) fusion proteins associated with cytosolic membrane structures that underwent movement, fusion and fission events. Overexpression of full-length APPL-YFP fusion proteins was sufficient to recruit endogenous RAB5 to enlarged APPL-associated membrane structures, although APPL1 was not necessary for RAB5 membrane targeting. Taken together, our findings suggest a role for APPL proteins as dynamic scaffolds that modulate RAB5-associated signaling endosomal membranes by their ability to undergo domain-mediated oligomerization, membrane targeting and phosphoinositide binding. 相似文献
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96.
Stephen McPhail 《仿生工程学报(英文版)》2009,6(1):55-62
With an ultimate range up to 1000 km,a maximum operating depth of 6000 m,and a generous payload capacity,Autosub6000is well placed to become one of the world’s most capable deep diving Autonomous Underwater Vehicles(AUVs).Recently,Autosub6000 successfully completed its first deep water engineering trials,and in September 2008,fitted with amultibeam sonar,will carry out its first science missions.This paper will describe how we are tackling the design issues thatspecifically affect a deep diving AUV which must be capable of operating with true autonomy,independently of the mother ship,namely:carrying adequate energy for long endurance and range,coping with varying buoyancy,and maintaining accuratenavigation throughout missions lasting up to several days.Results from the recent engineering trails are presented,and futuremissions and development plans are discussed. 相似文献
97.
The NADPH oxidase of human polymorphonuclear leukocytes. Evidence for regulation by multiple signals 总被引:14,自引:0,他引:14
Activation of the membrane-bound NADPH oxidase in human polymorphonuclear leukocytes can be triggered by chemoattractants, the tumor promoter phorbol myristate acetate or the calcium ionophore A23187. We have shown previously that these stimuli have markedly different temporal patterns of oxidase activation (McPhail, L. C., and Snyderman, R. (1983) J. Clin. Invest. 72, 192-200), suggesting that each follows, at least in part, a unique transductional pathway. We now report that if leukocytes were sequentially exposed to any of several combinations of heterologous stimuli, the pattern of activation by the second stimulus was strikingly altered, resulting in a more rapid rate and enhanced level of oxidase activation by the second stimulus. This suggests that exposure of cells to the first stimulus (priming) had influenced an intermediate also used by the second stimulus. The signal for priming could be clearly distinguished from the signal causing oxidase activation by the dose-response curves for each, as well as by the use of several pharmacologic agents. In addition, if leukocytes were given sequential doses of homologous stimuli, either partial (phorbol myristate acetate) or full (N-formyl-methionyl-leucyl -phenylalanine and A23187) desensitization of oxidase activation was observed. These results demonstrate that these stimuli share a common intermediate in the pathway of oxidase activation. Moreover, the data indicate that NADPH oxidase activation is regulated by at least three distinct signals: signal 1 (priming), signal 2 (activation), and signal 3 (inactivation). It is likely that more than one intracellular messenger exerts a modulating influence on NADPH oxidase activity and that its regulation involves the interplay between several cellular control proteins. 相似文献
98.
Phylogenetic relationships of bolitoglossine salamanders: a demonstration of the effects of combining morphological and molecular data sets 总被引:2,自引:0,他引:2
We analyzed sequence data for 555 bp of the mitochondrial gene cytochrome b
in plethodontid salamanders, taken from 18 ingroup (tribe Bolitoglossini)
and 4 outgroup (tribe Plethodontini) taxa. There were 257 variable sites,
of which 219 were phylogenetically informative. Sequence differences among
taxa exceeded 20%, and there were up to 15% amino acid differences among
the sequences. We also analyzed 37 morphological (including karyological)
characters, taken from the literature. Data were analyzed separately and
then combined using parsimony and likelihood approaches. There is little
conflict between the morphological and DNA data, and that which occurs is
at nodes that are weakly supported by one or both of the data sets. Treated
separately, the morphological and DNA data provide strong support for some
nodes but not for others. The combined data act synergistically so that
good support is obtained for nearly all of the nodes in the tree. Recent
divergences are supported by silent transitions, and older divergences are
supported by a combination of morphological, karyological, DNA
transversion, and amino acid changes. Eliminating silent changes from the
DNA data improves the consistency index and improves some bootstrap and
decay index values for several deeper branches in the tree. However, the
combined data set with all characters included provides a better supported
tree overall. Maximum likelihood and parsimony with all of the data give
not only the same topology but also remarkably similar branch lengths.
Results of this analysis support the monopoly of the supergenera
Hydromantes and Batrachoseps, and of a sister group relationship of
Batrachoseps and the supergenus Bolitoglossa (represented in this study one
species of the genus Bolitoglossa).
相似文献
99.
Digambaranath JL Campbell TV Chung A McPhail MJ Stevenson KE Zohdy MA Finke JM 《Proteins》2011,79(5):1427-1440
Polyglutamine repeats in proteins are highly correlated with amyloid formation and neurological disease. To better understand the molecular basis of glutamine repeat diseases, structural analysis of polyglutamine peptides as soluble monomers, oligomers, and insoluble amyloid fibrils is necessary. In this study, fluorescence resonance energy transfer (FRET) experiments and molecular dynamics simulations using different theoretical models of polyglutamine were conducted. This study demonstrates that a previously proposed simple C(α)C(β) model of polyglutamine, denoted as FCO, accurately reproduced the present FRET results and the results of previously published FRET, triplet-state quenching, and fluorescence correlation studies. Other simple C(α)C(β) models with random coil and extended β-strand parameters, and all-atom models with parm96 and parm99SB force fields, did not match the FRET result well. The FCO is an intrinsically disordered model with a high-effective persistence length producing extended peptides at short lengths (Q(N) < 10). Because of an increasing number of attractive Q-Q interactions at longer lengths, the FCO model becomes increasingly more compact at lengths between Q(N) ~ 10-16 and is as compact as many folded proteins at Q(N) > 16. 相似文献
100.
Asberom T Zhao Z Bara TA Clader JW Greenlee WJ Hyde LA Josien HB Li W McPhail AT Nomeir AA Parker EM Rajagopalan M Song L Wong GT Zhang L Zhang Q Pissarnitski DA 《Bioorganic & medicinal chemistry letters》2007,17(2):511-516
Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk. 相似文献