Current Protein and Peptide Science - Volume 10, Issue 5, 2009

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β-Lactamases are the greatest single source of resistance to β-lactam antibiotics. For over 60 years, clinicians have seen a pattern whereby useful new β-lactam analogues are introduced but then select for new β-lactamases that cause resistance. Thus, penicillin G was undermined by swift accumulation of staphylococcal penicillinase, ampicillin by TEM- 1 enzyme and modern oxymino cephalosporins by “extended-spectrum Read More

The discovery that the mechanism of β-lactam hydrolysis catalyzed by the class A (active site serinedependent) β-lactamases proceeds via an acyl-enzyme intermediate was made thirty years ago. Since this discovery, the active site circumstance that enables acylation of the active site serine and further enables hydrolytic deacylation of the acyl-serine intermediate, has received extraordinary scrutiny. The justification for this s Read More

Knowledge of the existence and structure of intermediates on the reaction pathway is necessary before specific details of the mechanism may be successfully resolved. However, enzymatic catalysis is an extremely fast process. This rapidity of enzyme-catalyzed reactions and the short life times of intermediates represent a major problem in studying the dynamic processes which occur during catalysis, as they prevent the Read More

During the past thirty years significant contributions to our understanding of the structural origins of the catalytic power of enzymes have come from solution and crystallographic studies of enzyme-substrate and enzymeintermediate complexes trapped at subzero temperatures, a field that was pioneered in large part by Anthony L. Fink and Pierre Douzou. Here I review, from a personal perspective, the history of crystallogra Read More

In a Nature article published in 1993, Anthony L. Fink and colleagues reported how Hsp70 chaperones use ATP binding in the presence of K+, rather than hydrolysis, to accelerate substrate release. As of the summer of 2008, his article had received 297 citations. I discuss here the influence Tony's iconic article has had on the chaperone field.

Stress, molecular crowding and mutations may jeopardize the native folding of proteins. Misfolded and aggregated proteins not only loose their biological activity, but may also disturb protein homeostasis, damage membranes and induce apoptosis. Here, we review the role of molecular chaperones as a network of cellular defences against the formation of cytotoxic protein aggregates. Chaperones favour the native foldi Read More

The structure of a globular protein is known to be affected by addition of acids or alkalis. The fact that a protein unfolds or at least denatures in solutions with extreme pH values was known for a long time. Prof. Anthony L. Fink (Tony) brought this field to a new level by showing that acid-unfolded proteins can partially regain their ordered structures in the presence of various anions. This review analyses his contributions t Read More

Protein aggregation, being one of the hottest topics of modern protein science, is recognized now as a serious biomedical and biotechnological problem. Protein aggregation is considered as a causative factor (or at least an associated symptom) of a wide spectrum of human pathologies. Furthermore, aggregation and precipitation are known to trammel recombinant protein production, as well as to affect the manufacture Read More

In a 1998 collaboration with Tony Fink, we coupled nanosecond circular dichroism methods (TRCD) with a CO-photolysis system for quickly triggering folding in cytochrome c (cyt c) in order to make the first time-resolved far- UV CD measurement of early secondary structure formation in a protein. The small signal observed in that initial study, ∼10% of native helicity, became the seed for increasingly robust results from Read More

When caused by multiplication mutations of its gene, increased expression of α-synuclein is associated with familial parkinsonism. Here we discuss the possibility that other mechanisms of α-synuclein elevation contribute to the pathogenesis of idiopathic, sporadic Parkinson's disease and other human synucleinopathies. Environmental (e.g. toxic exposures) and genetic (e.g. gene polymorphisms) risk factors, on the background Read More

Parkinson's disease (PD) is a slowly progressive movement disorder that results from the loss of dopaminergic neurons in the substantia nigra, a small area of cells in the mid-brain. PD is a multifactorial disorder with unknown etiology, in which both genetic and environmental factors play important roles. Substantial evidence links α-synuclein, a small highly conserved presynaptic protein with unknown function, to both fam Read More

Systemic light chain amyloidosis (AL) is one of several protein misfolding diseases and is characterized by extracellular deposition of immunoglobulin light chains in the form of amyloid fibrils [1]. Immunoglobulin (Ig) proteins consist of two light chains (LCs) and two heavy chains (HCs) that ordinarily form a heterotetramer which is secreted by a plasma cell. In AL, however, a monoclonal plasma cell population pro Read More

The therapeutic importance of gaining a thorough knowledge on insulin fibrillation in relation to type I diabetes has lead to six decades of studies focusing on its formation kinetics and structural characteristics. Insulin fibrils feature characteristics common to amyloid fibrils such as an elongated morphology, characteristic cross-β diffraction pattern, Thioflavin T fluorescence, and Congo Red birefringence. A full understa Read More

Current research suggests that the function of the prion protein (PrP) is linked to its ability to bind copper. PrP is implicated in copper regulation, copper buffering and copper-dependent signaling. Moreover, in the development of prion disease, copper may modulate the rate of protein misfolding. PrP possesses a number of copper sites, each with distinct chemical characteristics. Most studies thus far have concentrated Read More