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361.
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Swati Dubey Puja Majumder Aravind Penmatsa Abhijit A. Sardesai 《The Journal of biological chemistry》2021,297(4)
LysO, a prototypical member of the LysO family, mediates export of L-lysine (Lys) and resistance to the toxic Lys antimetabolite, L-thialysine (Thl) in Escherichia coli. Here, we have addressed unknown aspects of LysO function pertaining to its membrane topology and the mechanism by which it mediates Lys/Thl export. Using substituted cysteine (Cys) accessibility, here we delineated the membrane topology of LysO. Our studies support a model in which both the N- and C-termini of LysO are present at the periplasmic face of the membrane with a transmembrane (TM) domain comprising eight TM segments (TMSs) between them. In addition, a feature of intramembrane solvent exposure in LysO is inferred with the identification of membrane-located solvent-exposed Cys residues. Isosteric substitutions of a pair of conserved acidic residues, one E233, located in the solvent-exposed TMS7 and the other D261, in a solvent-exposed intramembrane segment located between TMS7 and TMS8, abolished LysO function in vivo. Thl, but not Lys, elicited proton release in inside-out membrane vesicles, a process requiring the presence of both E233 and D261. We postulate that Thl may be exported in antiport with H+ and that Lys may be a low-affinity export substrate. Our findings are compatible with a physiological scenario wherein in vivo LysO exports the naturally occurring antimetabolite Thl with higher affinity over the essential cellular metabolite Lys, thus affording protection from Thl toxicity and limiting wasteful export of Lys. 相似文献
363.
Eukaryotes encode numerous proteins that either have no detectable homologs in prokaryotes or have only distant homologs. These molecular innovations of eukaryotes may be classified into three categories: proteins and domains inherited from prokaryotic precursors without drastic changes in biochemical function, but often recruited for novel roles in eukaryotes; new superfamilies or distinct biochemical functions emerging within pre-existing protein folds; and domains with genuinely new folds, apparently 'invented' at the outset of eukaryotic evolution. Most new folds emerging in eukaryotes are either alpha-helical or stabilized by metal chelation. Comparative genomics analyses point to an early phase of rapid evolution, and dramatic changes between the origin of the eukaryotic cell and the advent of the last common ancestor of extant eukaryotes. Extensive duplication of numerous genes, with subsequent functional diversification, is a distinctive feature of this turbulent era. Evolutionary analysis of ancient eukaryotic proteins is generally compatible with a two-symbiont scenario for eukaryotic origin, involving an alpha-proteobacterium (the ancestor of the mitochondria) and an archaeon, as well as key contributions from their selfish elements. 相似文献
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One-electron reduction of S-nitrosothiols (RSNO) has been studied using radiolytically produced reducing entity, the hydrated electron (e(aq)(-)), in aqueous medium. Both kinetics of the reaction and the mechanistic aspects of the decomposition of S-nitroso derivatives of glutathione, L-cysteine, N-acetyl-L-cysteine, N-acetyl-D,L-penicillamine, N-acetylcysteamine, L-cysteine methyl ester, and D,L-penicillamine have been investigated at neutral and acidic pH. The second-order rate constants of the reaction of e(aq)(-) with RSNOs were determined using a pulse radiolysis technique and were found to be diffusion controlled (10(10) dm(3) mol(-1) s(-1)) at neutral pH. The product analysis using HPLC, fluorimetry, and MS revealed the formation of thiol and nitric oxide as the major end products. It is therefore proposed that one-electron reduction of RSNO leads to the liberation of NO. There is no intermediacy of a thiyl radical as in the case of oxidation reactions of RSNOs. The radical anion of RSNO (RSN(*)O(-)) is proposed as a possible intermediate. The overall reaction could be written as RSNO + e(aq)(-) --H+--> RSH + (*)NO. 相似文献
366.
Polymers, including biomolecules such as proteins, have two particularly important types of single-molecule transitions: a helix-coil transition, driven by interactions that are local in the chain, and a collapse transition, driven by nonlocal interactions. A long-standing challenge of polymer statistical mechanics has been to deal with both types of transition in a single theoretical framework. The simplest paradigmatic problem would be a theory of helix-bundle folding. Here, we show how the machinery of formal grammars, originally developed in the context of linguistic analysis and programming-language compilation, provides a simple and general way to combine the Zimm-Bragg model of alpha-helices with the model of Chen and Dill for nonlocal interactions in antiparallel polymeric systems. We use a well-known construction in the theory of formal grammars to give the statistical mechanical partition function for two-helix bundles. Predictions are shown to be quite good in comparison to exact enumerations within a lattice model. 相似文献
367.
Xu L Shen SS Hoshida Y Subramanian A Ross K Brunet JP Wagner SN Ramaswamy S Mesirov JP Hynes RO 《Molecular cancer research : MCR》2008,6(5):760-769
Metastasis is the deadliest phase of cancer progression. Experimental models using immunodeficient mice have been used to gain insights into the mechanisms of metastasis. We report here the identification of a "metastasis aggressiveness gene expression signature" derived using human melanoma cells selected based on their metastatic potentials in a xenotransplant metastasis model. Comparison with expression data from human melanoma patients shows that this metastasis gene signature correlates with the aggressiveness of melanoma metastases in human patients. Many genes encoding secreted and membrane proteins are included in the signature, suggesting the importance of tumor-microenvironment interactions during metastasis. 相似文献
368.
The haloacid dehalogenase (HAD) superfamily is a large family of proteins dominated by phosphotransferases. Thirty-three sequence families within the HAD superfamily (HADSF) have been identified to assist in function assignment. One such family includes the enzyme phosphoacetaldehyde hydrolase (phosphonatase). Phosphonatase possesses the conserved Rossmanniod core domain and a C1-type cap domain. Other members of this family do not possess a cap domain and because the cap domain of phosphonatase plays an important role in active site desolvation and catalysis, the function of the capless family members must be unique. A representative of the capless subfamily, PSPTO_2114, from the plant pathogen Pseudomonas syringae, was targeted for catalytic activity and structure analyses. The X-ray structure of PSPTO_2114 reveals a capless homodimer that conserves some but not all of the intersubunit contacts contributed by the core domains of the phosphonatase homodimer. The region of the PSPTO_2114 that corresponds to the catalytic scaffold of phosphonatase (and other HAD phosphotransfereases) positions amino acid residues that are ill suited for Mg+2 cofactor binding and mediation of phosphoryl group transfer between donor and acceptor substrates. The absence of phosphotransferase activity in PSPTO_2114 was confirmed by kinetic assays. To explore PSPTO_2114 function, the conservation of sequence motifs extending outside of the HADSF catalytic scaffold was examined. The stringently conserved residues among PSPTO_2114 homologs were mapped onto the PSPTO_2114 three-dimensional structure to identify a surface region unique to the family members that do not possess a cap domain. The hypothesis that this region is used in protein-protein recognition is explored to define, for the first time, HADSF proteins which have acquired a function other than that of a catalyst. 相似文献
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