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26 Ribonuclease A suggests how proteins self-chaperone against amyloid fiber formation

  1. Top of page
  2. 26 Ribonuclease A suggests how proteins self-chaperone against amyloid fiber formation
  3. 97 Revisiting the folding kinetics of bacteriorhodopsin
  4. 13 Signal peptidase I: Cleaving the way to mature proteins
  5. 84 Inward facing conformations of the MetNI methionine ABC transporter: Implications for the mechanism of transinhibition
  6. 1 Anthrax toxin protective antigen—Insights into molecular switching from prepore to pore

Poh K. Teng, Natalie J. Anderson, Lukasz Goldschmidt, Michael R. Sawaya, Shilpa Sambashivan, and David Eisenberg

Amyloids are fibrillous aggregates associated with neurodegenerative diseases that arise from proteins which self-aggregate via fibril-forming segments. Genomic analyses have identified fibril-forming segments in many proteins that do not form amyloid. Among these proteins is ribonuclease A (RNase A), which does not fibrillize in myriad conditions despite containing six fibril-forming segments. Molecular chaperones protect proteins from entering the amyloid state by permitting them to fold in isolation from identical molecules, but how do proteins self-chaperone their folding in the absence of accessory proteins? In this study, the authors convert RNase A into fibrils by increasing the conformational freedom of a fibril-forming segment SSTSAASS; Gly residues were inserted to sandwich this segment. These fibrils display biophysical properties resembling amyloids. RNase A appears to limit the conformational freedom of this fibril-forming segment from aggregating toward the amyloid state, suggesting that proteins have evolved to self-chaperone by limiting the conformational freedom of fibril-forming segments within their native sequences.

97 Revisiting the folding kinetics of bacteriorhodopsin

  1. Top of page
  2. 26 Ribonuclease A suggests how proteins self-chaperone against amyloid fiber formation
  3. 97 Revisiting the folding kinetics of bacteriorhodopsin
  4. 13 Signal peptidase I: Cleaving the way to mature proteins
  5. 84 Inward facing conformations of the MetNI methionine ABC transporter: Implications for the mechanism of transinhibition
  6. 1 Anthrax toxin protective antigen—Insights into molecular switching from prepore to pore

Jonathan P. Schlebach, Zheng Cao, James U. Bowie, and Chiwook Park

Investigations of the folding and unfolding of bacteriorhodopsin (bR) in mixed micelles have yielded key insights into the folding and stability of α-helical membrane proteins. Previously, it was believed that the folding energetics of bR were dependent simply on the fraction of denaturing detergent SDS in mixed micelles (XSDS). However, Schlebach et al. found that the folding rate of bR is strongly dependent on the number of mixed micelles as well. When the number of micelles is fixed, bR folding is significantly slower than previous studies suggest. This surprising result highlights a new critical variable in the investigation of membrane protein folding.

13 Signal peptidase I: Cleaving the way to mature proteins

  1. Top of page
  2. 26 Ribonuclease A suggests how proteins self-chaperone against amyloid fiber formation
  3. 97 Revisiting the folding kinetics of bacteriorhodopsin
  4. 13 Signal peptidase I: Cleaving the way to mature proteins
  5. 84 Inward facing conformations of the MetNI methionine ABC transporter: Implications for the mechanism of transinhibition
  6. 1 Anthrax toxin protective antigen—Insights into molecular switching from prepore to pore

Sarah M. Auclair, Meera K. Bhanu, and Debra A. Kendall

Cleavage of the signal peptide from a secretory preprotein by signal peptidase I is an essential step in protein translocation and for cell viability. Signal peptidase I is an attractive target for the development of antimicrobial agents, because the eubacterial enzyme has a number of significant mechanistic differences compared with the eukaryotic enzyme. The advent of multidrug resistant bacterial strains has increased the demand for novel antibiotics to treat diseases worldwide. Understanding the details of how signal peptidase I functions is an essential step in the quest to develop potent inhibitors of the enzyme. This review highlights some recent advances in understanding how signal peptidase I functions and the discovery of a number of potential inhibitors.

84 Inward facing conformations of the MetNI methionine ABC transporter: Implications for the mechanism of transinhibition

  1. Top of page
  2. 26 Ribonuclease A suggests how proteins self-chaperone against amyloid fiber formation
  3. 97 Revisiting the folding kinetics of bacteriorhodopsin
  4. 13 Signal peptidase I: Cleaving the way to mature proteins
  5. 84 Inward facing conformations of the MetNI methionine ABC transporter: Implications for the mechanism of transinhibition
  6. 1 Anthrax toxin protective antigen—Insights into molecular switching from prepore to pore

Eric Johnson, Phong T. Nguyen, Todd O. Yeates, and Douglas C. Rees

Cellular homeostasis is vitally dependent on the regulation of transport across membranes. Recent crystal structures of the MetNI Escherichia coli high affinity methionine importer (an ATP Binding Cassette transporter) provide insights into the mechanism for regulating transporter activity in response to intracellular methionine levels. The structures capture this transporter in alternate conformational states; a ligand free “on” state and a transinhibited “switched off” state corresponding to the binding of inhibitory methionine ligand to the regulatory domains. The authors suggest a potential coupling of ligand binding to a switch between alternate discrete conformational states involving a change in β-strand register at the dimer interface between regulatory domains.

1 Anthrax toxin protective antigen—Insights into molecular switching from prepore to pore

  1. Top of page
  2. 26 Ribonuclease A suggests how proteins self-chaperone against amyloid fiber formation
  3. 97 Revisiting the folding kinetics of bacteriorhodopsin
  4. 13 Signal peptidase I: Cleaving the way to mature proteins
  5. 84 Inward facing conformations of the MetNI methionine ABC transporter: Implications for the mechanism of transinhibition
  6. 1 Anthrax toxin protective antigen—Insights into molecular switching from prepore to pore

James G. Bann

One of the key events in the pathogenesis of anthrax is the formation of a membrane-spanning pore by protective antigen (PA), a component of the anthrax toxin. Pore formation occurs at acidic pH within the cell, and identifying amino acid residues in PA that are important for this process has been the focus of much research. Here, the author reviews the available biochemical literature and presents a kinetic model in which pore formation is initiated by the formation of the phi (φ)-clamp, a region that is critical for the translocation of the enzymatic moieties of the toxin into the cell.