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Journal Issue - Volume 15 Issue 8 (August 2006)

Abstract ATP‐dependent Lon proteases are multi‐domain enzymes found in all living organisms. All Lon proteases contain an ATPase domain belonging to the AAA+ superfamily of molecular machines and a proteolytic domain with a serine‐lysine catalytic dyad. Lon proteases can be divided into two subfamilies, LonA and LonB, exemplified by the Escherichia coli and Archaeoglobus fulgidus paralogs, respectively. The LonA subfamily is defined by the...

Abstract Using a test set of 13 small, compact proteins, we demonstrate that a remarkably simple protocol can capture native topology from secondary structure information alone, in the absence of long‐range interactions. It has been a long‐standing open question whether such information is sufficient to determine a protein's fold. Indeed, even the far simpler problem of reconstructing the three‐dimensional structure of a protein...

Abstract The inability to determine the structure of the buffer‐insoluble Nogo extracellular domain retarded further design of Nogo receptor (NgR) antagonists to treat CNS axonal injuries. Very surprisingly, we recently discovered that Nogo‐60 was soluble and structured in salt‐free water, thus allowing the determination of the first Nogo structure by heteronuclear NMR spectroscopy. Nogo‐60 adopts an unusual helical structure with...

Abstract Methionine aminopeptidases (MetAPs) remove the initiator methionine during protein biosynthesis. They exist in two isoforms, MetAP1 and MetAP2. The anti‐angiogenic compound fumagillin binds tightly to the Type 2 MetAPs but only weakly to Type 1. High‐affinity complexes of fumagillin and its relative ovalicin with Type 2 human MetAP have been reported. Here we describe the crystallographic structure of the low‐affinity...

  • Crystal structures of saposins A and C

  • Victoria E. Ahn, Paul Leyko, Jean‐René Alattia, Lu Chen, Gilbert G. Privé
  • Published in Wiley Interscience on Jan 01, 2009
  • DOI: 10.1110/ps.062256606 (p 1849-1857)

Abstract Saposins A and C are sphingolipid activator proteins required for the lysosomal breakdown of galactosylceramide and glucosylceramide, respectively. The saposins interact with lipids, leading to an enhanced accessibility of the lipid headgroups to their cognate hydrolases. We have determined the crystal structures of human saposins A and C to 2.0 Å and 2.4 Å, respectively, and both reveal the compact, monomeric saposin fold....

Abstract Although core residues can sometimes be replaced by shorter ones without introducing significant changes in protein structure, the energetic consequences are typically large and destabilizing. Many efforts have been devoted to understand and predict changes in stability from analysis of the environment of mutated residues, but the relationships proposed for individual proteins have often failed to describe additional data....

Abstract Phosphoinositides (PIs) are concentrated in specific subcellular membranes in order to recruit and regulate cytosolic proteins responsible for vesicular trafficking, cytoskeletal rearrangement, and eukaryotic cell growth, differentiation, and survival. Phox homology (PX) domains are found in proteins that are integral players in endocytic pathways. For example, Vam7p is targeted by its PX domain to phosphatidylinositol...

Abstract A nuclear receptor, peroxisome proliferator‐activated receptor γ (PPARγ), is a ligand‐dependent transcription factor involved in glucose homeostasis and adipocyte differentiation. PPARγ is the molecular target of various natural and synthetic molecules, including anti‐diabetic agents such as rosiglitazone. Amide hydrogen/deuterium‐exchange (H/D‐Ex), coupled with proteolysis and mass spectrometry, was applied to study the...

Abstract This study tested the hypothesis that high‐affinity binding of macromolecular ligands to the αIIbβ3 integrin is tightly coupled to binding‐site remodeling, an induced‐fit process that shifts a conformational equilibrium from a resting toward an open receptor. Interactions between αIIbβ3 and two model ligands—echistatin, a 6‐kDa recombinant protein with an RGD integrin‐targeting sequence, and fibrinogen's γ‐module, a 30‐kDa...

Abstract Outer surface protein A (OspA) from Borrelia burgdorferi has an unusual dumbbell‐shaped structure in which two globular domains are connected with a “single‐layer” β‐sheet (SLB). The protein is highly soluble, and it has been recalcitrant to crystallization. Only OspA complexes with Fab fragments have been successfully crystallized. OspA contains a large number of Lys and Glu residues, and these “high entropy” residues may ...

Abstract In this work we compare the dynamics and conformational stability of Pseudomonas mendocina lipase enzyme and its F180P/S205G mutant that shows higher activity and stability for use in washing powders. Our NMR analyses indicate virtually identical structures but reveal remarkable differences in local dynamics, with striking correspondence between experimental data (i.e., 15N relaxation and H/D exchange rates) and data from Molecular...

Abstract Enzyme‐catalyzed addition of biotin to proteins is highly specific. In any single organism one or a small number of proteins are biotinylated and only a single lysine on each of these proteins is modified. A detailed understanding of the structural basis for the selective biotinylation process has not yet been elucidated. Recently certain mutants of the Escherichia coli biotin protein ligase have been shown to mediate “promiscuous”...

Abstract Development of biosensor devices typically requires incorporation of the molecular recognition element into a solid surface for interfacing with a signal detector. One approach is to immobilize the signal transducing protein directly on a solid surface. Here we compare the effects of two direct immobilization methods on ligand binding, kinetics, and signal transduction of reagentless fluorescent biosensors based on...

Abstract An active site containing a CXXC motif is always found in the thiol‐disulphide oxidoreductase superfamily. A survey of crystal structures revealed that the CXXC motif had a very high local propensity (26.3 ± 6.2) for the N termini of α‐helices. A helical peptide with the sequence CAAC at the N terminus was synthesized to examine the helix‐stabilizing capacity of the CXXC motif. Circular dichroism was used to confirm the...

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