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The 3D structure of a protein is determined by the unique sequence of amino acid residues comprising the polypeptide chain. Sequence changes can cause protein misfolding, a potentially toxic phenomenon implicated in various neurodegenerative disorders. In a recent paper, translational misincorporation is proposed to be a new biochemical mechanism for generating mutant proteins that misfold and kill neurons.
ACS Chem Biol 2006 Oct 24
PMID:Errors in translation cause selective neurodegeneration. 1716 50

The S24F mutant of the chemokine RANTES was found to be partly acetylated when produced in recombinant Escherichia coli BL21(DE3)(pDIA17)(CCL5-S24F-pET-26b). Mass spectrometry and Edman sequencing of peptides generated by lys-C endopeptidase indicated that Lys-26, Lys-34, Lys-46, and Lys-57 were susceptible to acetylation. The extent of acetylation of the RANTES S24F polypeptide increased with temperature and with the time during which the culture was incubated after adding the inducer isopropyl-beta-D-thiogalactoside (IPTG). These findings suggest that induction at low temperature and for a short period of time should be preferred when spurious acetylation is a problem for the production of genuine recombinant polypeptides. Acetylation of the polypeptide was not affected by deleting acs, yfiQ, or speG, which encode acetyl-CoA synthetase, acetyl-CoA synthetase acetylase, and spermidine acetyl transferase, respectively, nor by the presence or absence of the pDIA17 plasmid, which harbours the cat gene encoding chloramphenicol acetyl transferase. By contrast, spontaneous acetylation of RANTES could be demonstrated by incubating either the purified polypeptide or inclusion bodies derived from an induced culture in the presence of acetyl-CoA.
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PMID:Time- and temperature-dependent acetylation of the chemokine RANTES produced in recombinant Escherichia coli. 1757 62

The Omp85/YaeT family of proteins, which are conserved from bacteria to human, catalyzes insertion and assembly of proteins in the outer membrane. The structure consists of a transmembrane beta-barrel domain and a soluble polypeptide-transport-associated (POTRA) domain. The POTRA domain is critical for substrate recognition and perhaps substrate folding, while the beta-barrel domain assists in membrane insertion. The resolution of the crystal structure of the POTRA domain of the Escherichia coli YaeT protein provides a possible molecular mechanism by which the diverse group of substrates is recognized. Knowledge gained from the crystal structure may also spur the development of a novel class of chemotherapeutic inhibitors.
ACS Chem Biol 2007 Oct 19
PMID:First glimpse of the crystal structure of YaeT's POTRA domains. 1804 13

There are several approaches to creating synthetic-biological systems. Here, we describe a molecular-design approach. First, we lay out a possible synthetic-biology space, which we define with a plot of complexity of components versus divergence from nature. In this scheme, there are basic units, which range from natural amino acids to totally synthetic small molecules. These are linked together to form programmable tectons, for example, amphipathic alpha-helices. In turn, tectons can interact to give self-assembled units, which can combine and organize further to produce functional assemblies and systems. To illustrate one path through this vast landscape, we focus on protein engineering and design. We describe how, for certain protein-folding motifs, polypeptide chains can be instructed to fold. These folds can be combined to give structured complexes, and function can be incorporated through computational design. Finally, we describe how protein-based systems may be encapsulated to control and investigate their functions.
ACS Chem Biol 2008 Jan 18
PMID:Peptide and protein building blocks for synthetic biology: from programming biomolecules to self-organized biomolecular systems. 1820 91

Brain-derived neurotrophic factor (BDNF) is a polypeptide that is secreted from neurons. Although there is mounting evidence that BDNF regulates neuronal development and synaptic plasticity, BDNF secretion has remained unclear due to lack of appropriate methods for the analysis of its dynamics. To visualize BDNF secretion from neurons, here we have developed a cell-based fluorescent indicator for BDNF. We showed that the present cell-based fluorescent indicator, named "Bescell", has high selectivity to BDNF and detects picomolar concentrations of BDNF (detection limit of 60 pM). Bescell has visualized endogenous BDNF secreted from hippocampal neurons. It thus provides a powerful tool for the analysis of BDNF secretion from living neurons.
ACS Chem Biol 2008 Jun 20
PMID:Cell-based fluorescent indicator to visualize brain-derived neurotrophic factor secreted from living neurons. 1851 Mar 13

Very little is known about the conformation of polypeptides emerging from the ribosome during protein biosynthesis. Here, we explore the dynamics of ribosome-bound nascent polypeptides and proteins in Escherichia coli by dynamic fluorescence depolarization and assess the population of cotranslationally active chaperones trigger factor (TF) and DnaK. E. coli cell-free technology and fluorophore-linked E. coli Met-tRNA f Met enable selective site-specific labeling of nascent proteins at the N-terminal methionine. For the first time, direct spectroscopic evidence captures the generation of independent nascent chain motions for a single-domain protein emerging from the ribosome (apparent rotational correlation time approximately 5 ns), during the intermediate and late stages of polypeptide elongation. Such motions are detected only for a sequence encoding a globular protein and not for a natively unfolded control, suggesting that the independent nascent chain dynamics may be a signature of folding-competent sequences. In summary, we observe multicomponent, severely rotationally restricted, and strongly chain length/sequence-dependent nascent chain dynamics.
ACS Chem Biol 2008 Sep 19
PMID:Chain dynamics of nascent polypeptides emerging from the ribosome. 1880 69

Deciphering the mechanism of folding of newly synthesized proteins in the cell is a major challenge because of the large size and multiplicity of molecular components involved and the asynchrony of biosynthesis. Fluorescently labeled ribosome-bound nascent chains of a defined length were prepared and subjected to dynamic fluorescence depolarization spectroscopy measurements. Nanosecond anisotropy decay correlation times of proteins' nascent chains at different stages of polypeptide elongation were determined for the first time. Striking dependence of the chain dynamics on the stages of elongation was observed and revealed chain length dependence of folding on the ribosome.
ACS Chem Biol 2008 Sep 19
PMID:Folding on the assembly line. 1871 65

Prosthesis of non-critical parts of a polypeptide backbone is an attractive strategy to simplify bioactive peptides. This approach was applied to an opioid neuropeptide, Met-enkephalin, in which two adjacent Gly2-Gly3 residues were replaced with a series of non-peptidic backbone spacers varying in length and/or physicochemical properties. The backbone spacers did not affect the overall structural properties of the analogues, but they did dramatically reduce their affinities and agonist activities toward delta- and mu-opioid receptors. Molecular modeling suggested that the decrease of the affinity of Met-enkephalin to delta-opioid receptor could be accounted for by the loss of a single hydrogen bond. Remarkably, the analogues containing the most isostere spacers retained potent antinociceptive and anticonvulsant properties that were comparable to that of the endogenous peptide. This unexpected high in vivo potency could not be accounted for by an increase in metabolic stability. Moreover, the antiepileptic activity could not be reversed by opioid receptor antagonists. In summary, the results obtained with the analogues containing backbone spacers suggest a novel mechanism for seizure control in the brain that involves alternative non-opioid signaling.
ACS Chem Biol 2009 Aug 21
PMID:Anticonvulsant Met-enkephalin analogues containing backbone spacers reveal alternative non-opioid signaling in the brain. 1963 61

A method is described for the site-directed manipulation of single filamentous bacteriophages, by using phage display technology and atomic force microscopy. f1 filamentous bacteriophages were genetically engineered to display His-tags on their pIX tail. Following adsorption on nitrilotriacetate-terminated surfaces, force spectroscopy with tips bearing monoclonal anti-pIII antibodies was used to pull on individual phages via their pIII head. Analysis of the force-extension profiles revealed that upon pulling, the phages are progressively straightened into an extended orientation until rupture of the anti-pIII/pIII complex. The single-virus manipulation technique presented here provides new opportunities for understanding the forces driving cell-virus and material-virus interactions, and for characterizing the binding properties of polypeptide sequences or proteins selected by the phage display technology.
ACS Nano 2009 Oct 27
PMID:Controlled manipulation of bacteriophages using single-virus force spectroscopy. 1976 81

An improved method for the semisynthesis of a potassium channel involving native chemical ligation allows the introduction of short sequences containing non-canonical amino acids at any position within the polypeptide chain. The work enhances the technology available for a range of fundamental investigations of membrane proteins and for applications of membrane channels and pores in biotechnology.
ACS Chem Biol 2009 Dec 18
PMID:Wrestling with native chemical ligation. 2001 75


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