The structure and function of platelet-activating factor acetylhydrolases

Platelet-activating factor acetylhydrolases (PAF-AHs, EC 3.1.1.47) constitute a unique and biologically important family of phospholipase A₂s. They are related to neither the well-characterized secretory nor cytosolic PLA₂s, and unlike them do not require Ca²⁺ for catalytic activity. The distinguishing property of PAF-AHs is their unique substrate specificity they act on the phospholipid platelet-activating factor (PAF), and in some cases on proinflammatory polar phospholipids, from which they remove a short acyl moiety – acetyl in the case of PAF – located at the sn-2 position. Because PAF is found both in the plasma and in the cytosol of many tissues, PAF-acetylhydrolases are equally widely distributed in an animal organism. Recent crystallographic studies shed new light on the complex structure-function relationships in PAF-AHs. Received 15 September 1997; received after revision 23 February 1998; accepted 25 February 1998     

Synthesis, structure and function of poly-α-amino acids – the simplest of protein models

During the 1950s, linear and multichain poly-α-amino acids were synthesized by polymerization of the corresponding N-carboxyamino acid anhydrides in solution in the presence of suitable catalysts. The resulting homo- and heteropolymers have since been widely employed as simple protein models. Under appropriate conditions, poly-α-amino acids, in the solid state and in solution, were found to acquire conformations of an α-helix and of β-parallel and antiparallel pleated sheets, or to exist as random coils. Their use in experimental and theoretical investigations of helix-coil transitions helped to shed new light on the mechanisms involved in protein denaturation. Conformational fluctuations of peptides in solution were analysed theoretically and studied experimentally by nonradiative energy-transfer techniques. Poly-α-amino acids played an important role in the deciphering of the genetic code. In addition, analysis of the antigenicity of poly-α-amino acids led to the elucidation of the factors determining the antigenicity of proteins and peptides. The synthetic procedures developed made possible the preparation of immobilized enzymes which were shown to be of considerable use as heterogeneous biocatalysts in the chemical and pharmaceutical industry. Interest in the biological and physicochemical characteristics of poly-α-amino acids was recently renewed because of the reported novel findings that some copolymers of amino acids are effective as drugs in multiple sclerosis, and that glutamine repeats and reiteration of other amino acids occur in inherited neurodegenerative diseases.     

AMP-activated protein kinase in skeletal muscle: From structure and localization to its role as a master regulator of cellular metabolism

The AMP-activated protein kinase (AMPK) is a metabolite sensing serine/threonine kinase that has been termed the master regulator of cellular energy metabolism due to its numerous roles in the regulation of glucose, lipid, and protein metabolism. In this review, we first summarize the current literature on a number of important aspects of AMPK in skeletal muscle. These include the following: (1) the structural components of the three AMPK subunits (i.e. AMPKα, β, and γ), and their differential localization in response to stimulation in muscle; (2) the biochemical regulation of AMPK by AMP, protein phosphatases, and its three known upstream kinases, LKB1, Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK), and transforming growth factor-β-activated kinase 1 (TAK1); (3) the pharmacological agents that are currently available for the activation and inhibition of AMPK; (4) the physiological stimuli that activate AMPK in muscle; and (5) the metabolic processes that AMPK regulates in skeletal muscle. Received 04 May 2008; received after revision 14 June 2008; accepted 14 July 2008     

Introduction: genetic determinants of mid- and late-life dementias

We introduce a series of papers dealing with genetic aspects of a subset of dementias of mid-life and late-life in order to illustrate four principles. First, there appear to be many genetic loci with the potential to modulate susceptibility to such dementias. Second, most of those so far discovered are autosomal dominants and none are autosomal recessives. Third, the autosomal dominant mutations are individually rare. Their frequencies in a given population are likely to be functions of genetic drift. Fourth, despite their rarity, they may inform us about the pathogenesis of more common late-life dementias, notably dementias of the Alzheimer type, which have polygenic determinants. The most important such modulation so far discovered involves polymorphic forms of the APOE locus.     

The V(D)J recombination activating protein RAG2 consists of a six-bladed propeller and a PHD fingerlike domain, as revealed by sequence analysis

The RAG1 and RAG2 proteins play a crucial role in V(D)J recombination by cooperating to make specific double-stranded DNA breaks at a pair of recombination signal sequences (RSSs). However, the exact function they perform has heretofore remained elusive. Using a combination of sensitive methods of sequence analysis, we show here that the active core region of the RAG2 protein, confined to the first three quarters of its sequence, is in fact composed of a six-fold repeat of a 50-residue motif which is related to the kelch/mipp motif. This motif, which forms a four-stranded twisted antiparallel β sheet, is arranged in a circular formation like blades of a propeller or turbine. Given the known properties of the β-propeller fold in mediating protein-protein interactions, it is proposed that this six-laded propeller structure of the RAG2 active core would play a crucial role in the tight complex formed by the RAG1 and RAG2 proteins and RSSs. Moreover, the presence of a plant homeodomain finger-like motif in the last quarter of the RAG2 sequence suggests a potential interaction of this domain with chromatin components. Received 6 June 1998; accepted 9 June 1998     

Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors

The Alzheimer’s amyloid precursor protein (APP) belongs to a conserved gene family that also includes the mammalian APLP1 and APLP2, the Drosophila APPL, and the C. elegans APL-1. The biological function of APP is still not fully clear. However, it is known that the APP family proteins have redundant and partly overlapping functions, which demonstrates the importance of studying all APP family members to gain a more complete picture. When APP was first cloned, it was speculated that it could function as a receptor. This theory has been further substantiated by studies showing that APP and its homologues bind both extracellular ligands and intracellular adaptor proteins. The APP family proteins undergo regulated intramembrane proteolysis (RIP), generating secreted and cytoplasmic fragments that have been ascribed different functions. In this review, we will discuss the APP family with focus on biological functions, binding partners, and regulated processing.