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Journal Issue - Volume 16 Issue 4 (April 2007)

Abstract Accumulation of chemically altered proteins is a noted characteristic of biological aging, and increasing evidence suggests a variety of deleterious cellular developments associated with senescence. Concomitantly, the “aging” of protein deposits associated with numerous neurological disorders may involve covalent modifications of their constituents. However, the link between disease‐related protein aggregation and chemical...

Abstract The core of the Abelson tyrosine kinase (c‐Abl) is structurally similar to Src‐family kinases where SH3 and SH2 domains pack against the backside of the kinase domain in the down‐regulated conformation. Both kinase families depend upon intramolecular association of SH3 with the linker joining the SH2 and kinase domains for suppression of kinase activity. Hydrogen deuterium exchange (HX) and mass spectrometry (MS) were used...

Abstract Lipid transfer proteins (LTPs) are a family of proteins that bind and transfer lipids. Utilizing the maize LTP, we have successfully engineered fluorescent reagentless biosensors for the natural ligand of LTPs; this was achieved by using computational protein design to remove a disulfide bridge and attaching a thio‐reactive fluorophore. Conformational change induced by ligand titration is thought to affect the fluorescence...

Abstract Dissimilatory oxidation of thiosulfate in the green sulfur bacterium Chlorobium limicola f. thiosulfatophilum is carried out by the ubiquitous sulfur‐oxidizing (Sox) multi‐enzyme system. In this system, SoxY plays a key role, functioning as the sulfur substrate‐binding protein that offers its sulfur substrate, which is covalently bound to a conserved C‐terminal cysteine, to another oxidizing Sox enzyme. Here, we report the crystal...

Abstract A key step in the signaling cascade responsible for activation of the transcription factor NF‐κB involves Lys63‐linked polyubiquitination of TRAF6. Covalent attachment of ubiquitin (Ub) to TRAF6, and subsequent poly(Ub) chain synthesis, is catalyzed by the hUev1a–hUbc13 heterodimer. hUbc13 is a catalytically competent E2 enzyme, and hUev1a is an E2‐like protein that binds substrate Ub. The hUev1a–hUbc13 heterodimer is...

Abstract The superfamily of eye lens βγ‐crystallins is highly modularized, with Greek key motifs being used to form symmetric domains. Sequences of monomeric γ‐crystallins and oligomeric β‐crystallins fold into two domains that pair about a further conserved symmetric interface. Conservation of this assembly interface by domain swapping is the device adopted by family member βB2‐crystallin to form a solution dimer. However, the...

Abstract Prefoldin is a molecular chaperone found in the domains eukarya and archaea that acts in conjunction with Group II chaperonin to correctly fold other nascent proteins. Previously, our group identified a putative single subunit of prefoldin, γ PFD, that was up‐regulated in response to heat stress in the hyperthermophilic archaeon Methanocaldococcus jannaschii. In order to characterize this protein, we subcloned and expressed it and the...

Abstract The fusion of soluble partner to the N terminus of aggregation‐prone polypeptide has been popularly used to overcome the formation of inclusion bodies in the E. coli cytosol. The chaperone‐like functions of the upstream fusion partner in the artificial multidomain proteins could occur in de novo folding of native multidomain proteins. Here, we show that the N‐terminal domains of three E. coli...

Abstract Chaperones and proteases share the ability to interact with unfolded proteins. Here we show that enzymatically inactive forms of the aspartic proteases HIV‐1 protease and pepsin have inherent chaperone‐like activity and can prevent the aggregation of denatured substrate proteins. In contrast to proteolysis, which requires dimeric enzymes, chaperone‐like activity could be observed also with monomeric domains. The involvement...

Abstract The E3 ubiquitin ligase neuregulin receptor degrading protein 1 (Nrdp1) mediates the ligand‐independent degradation of the epidermal growth factor receptor family member ErbB3/HER3. By regulating cellular levels of ErbB3, Nrdp1 influences ErbB3‐mediated signaling, which is essential for normal vertebrate development. Nrdp1 belongs to the tripartite or RBCC (RING, B‐box, coiled‐coil) family of ubiquitin ligases in which the...

Abstract The exchange of residues 67 and 205 of the S2 pocket of human cysteine cathepsins K and L induces a permutation of their substrate specificity toward fluorogenic peptide substrates. While the cathepsin L‐like cathepsin K (Tyr67Leu/Leu205Ala) mutant has a marked preference for Phe, the Leu67Tyr/Ala205Leu cathepsin L variant shows an effective cathepsin K‐like preference for Leu and Pro. A similar turnaround of inhibition was...

Abstract Coagulation factor VIIa (FVIIa) requires tissue factor (TF) to attain full catalytic competency and to initiate blood coagulation. In this study, the mechanism by which TF allosterically activates FVIIa is investigated by a structural dynamics approach that combines molecular dynamics (MD) simulations and hydrogen/deuterium exchange (HX) mass spectrometry on free and TF‐bound FVIIa. The differences in conformational...

Abstract PDZ domains are protein–protein interaction modules that generally bind to the C termini of their target proteins. The C‐terminal four amino acids of a prospective binding partner of a PDZ domain are typically the determinants of binding specificity. In an effort to determine the structures of a number of PDZ domains we have included appropriate four residue extensions on the C termini of PDZ domain truncation mutants,...

Abstract Apoptosis of virally infected cells is an innate host mechanism used to prevent viral spread. However, viruses have evolved a number of proteins that function to modulate the apoptotic cascades and thereby favor productive viral replication. One such antiapoptotic protein, myxoma virus M11L, has been shown to inhibit mitochondrial‐dependent apoptosis by binding to and blocking the two executioner proteins Bak and Bax. Since...

Abstract Diverse Gram‐negative bacteria use type III secretion systems (T3SS) to translocate effector proteins into the cytoplasm of eukaryotic cells. The type III secretion apparatus (T3SA) consists of a basal body spanning both bacterial membranes and an external needle. A sensor protein lies at the needle tip to detect environmental signals that trigger type III secretion. The Shigella flexneri T3SA needle tip protein, invasion...

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