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Journal Issue - Volume 15 Issue 11 (November 2006)

Abstract p53 modulates a large number of cellular response pathways and is critical for the prevention of cancer. Wild‐type p53, as well as tumorigenic mutants, exhibits the singular property of spontaneously losing DNA binding activity at 37°C. To understand the molecular basis for this effect, we examine the folding mechanism of the p53 DNA binding domain (DBD) at elevated temperatures. Folding kinetics do not change appreciably...

Abstract Understanding substrate specificity and identification of natural targets of transglutaminase 2 (TG2), the ubiquitous multifunctional cross‐linking enzyme, which forms isopeptide bonds between protein‐linked glutamine and lysine residues, is crucial in the elucidation of its physiological role. As a novel means of specificity analysis, we adapted the phage display technique to select glutamine‐donor substrates from a random...

Abstract The protein Ure2 from baker's yeast is associated with a heritable and transmissible phenotypic change in the yeast Saccharomyces cerevisiae. Such prion properties are thought to arise from the fact that Ure2p is able to self‐assemble into insoluble fibrils. Assemblies of Ure2p are composed of full‐length proteins in which the structure of the globular, functional, C‐terminal domain is retained. We have carried out structural studies...

Abstract Previously, we have shown that residues 73–92 (sequence DRFSVNLDVKHFSPEELKVK) in αB‐crystallin are involved in preventing the formation of light scattering aggregates by substrate proteins. In this study, we made single substitutions of three conserved amino acid residues (H83 → A, F84 → G, and P86 → A) and a nonconserved amino acid residue (K90 → C) in the functional region of αB‐crystallin and evaluated their role in...

Abstract The major aim of tertiary structure prediction is to obtain protein models with the highest possible accuracy. Fold recognition, homology modeling, and de novo prediction methods typically use predicted secondary structures as input, and all of these methods may significantly benefit from more accurate secondary structure predictions. Although there are many different secondary structure prediction methods available in the...

Abstract Protein structures in the Protein Data Bank provide a wealth of data about the interactions that determine the native states of proteins. Using the probability theory, we derive an atomic distance‐dependent statistical potential from a sample of native structures that does not depend on any adjustable parameters (Discrete Optimized Protein Energy, or DOPE). DOPE is based on an improved reference state that corresponds to...

Abstract A fast method for the calculation of residue contributions to protein solvation is presented. The approach uses the exposed polar and apolar surface of protein residues and has been parametrized from the fractional contributions to solvation determined from linear response theory coupled to molecular dynamics simulations. Application of the method to a large subset of proteins taken from the Protein Data Bank allowed us to...

Abstract Cyclophilins are proteins that catalyze X‐proline cis–trans interconversion, where X represents any amino acid. Its mechanism of action has been investigated over the past years but still generates discussion, especially because until recently structures of the ligand in the cis and trans conformations for the same system were lacking. X‐ray crystallographic structures for the complex cyclophilin A and HIV‐1 capsid mutants with ligands...

Abstract Amyloid formation is associated with structural changes of native polypeptides to monomeric intermediate states and their self‐assembly into insoluble aggregates. Characterizations of the amyloidogenic intermediate state are, therefore, of great importance in understanding the early stage of amyloidogenesis. Here, we present NMR investigations of the structural and dynamic properties of the acid‐unfolded amyloidogenic...

Abstract Discovery of discontinuous B‐cell epitopes is a major challenge in vaccine design. Previous epitope prediction methods have mostly been based on protein sequences and are not very effective. Here, we present DiscoTope, a novel method for discontinuous epitope prediction that uses protein three‐dimensional structural data. The method is based on amino acid statistics, spatial information, and surface accessibility in a...

Abstract SDF‐1α is a member of the chemokine family implicated in various reactions in the immune system. The interaction of SDF‐1α with its receptor, CXCR4, is responsible for metastasis of a variety of cancers. SDF‐1α is also known to play a role in HIV‐1 pathogenesis. The structures of SDF‐1α determined by NMR spectroscopy have been shown to be monomeric while X‐ray structures are dimeric. Biochemical data and in vivo studies...

Abstract The genome of the diurnal cyanobacterium Cyanothece sp. PCC 51142 has recently been sequenced and observed to contain 35 pentapeptide repeat proteins (PRPs). These proteins, while present throughout the prokaryotic and eukaryotic kingdoms, are most abundant in cyanobacteria. The sheer number of PRPs in cyanobacteria coupled with their predicted location in every cellular compartment argues for important, yet unknown, ...

Abstract The λ6‐85* pseudo‐wild type of lambda repressor fragment is a fast two‐state folder (kf ≈ 35 μsec−1 at 58°C). Previously, highly stable λ6‐85* mutants with kf > 30 μsec−1 have been engineered to fold nearly or fully downhill. Stabilization of the native state by solvent tuning might also tune λ6‐85* away from two‐state folding. We test this prediction by examining the folding thermodynamics and kinetics of λ6‐85* in a stabilizing solvent, 45%...

Abstract YciF is a protein that is up‐regulated when bacteria experience stress conditions, and is highly conserved in a range of bacterial species. YciF has no known structure or biochemical function. To learn more about its potential molecular function and its role in the bacterial stress response, we solved the crystal structure of YciF at 2.0 Å resolution by the multiple wavelength anomalous diffraction (MAD) technique. YciF is...

Abstract The study of protein–protein interactions can be hampered by the instability of one or more of the protein complex components. In this study, we showed that intein‐mediated cyclization can be used to engineer an artificial intramolecular cyclic protein complex between two interacting proteins: the largely unstable LIM‐only protein 4 (LMO4) and an unstructured domain of LIM domain binding protein 1 (ldb1). The X‐ray...

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