Molecular motors: not quite like clockwork

Models commonly used to explain the mechanism of myosin motors typically include a power stroke that is attributed to a conformational change in the motor domain and amplified by a long lever arm that connects the motor domain to the cargo. Similar models have proved less enlightening in the case of microtubule motors, for which it may be more helpful to consider models involving thermally driven mechanisms. Received 9 November 2007; received after revision 7 December 2007; accepted 11 December 2007     

Myosin I: From yeast to human

Myosin I is a non-filamentous, single-headed, actin-binding motor protein and is present in a wide range of species from yeast to man. The role of these class I myosins have been studied extensively in simple eukaryotes, showing their role in diverse processes such as actin cytoskeleton organization, cell motility, and endocytosis. Recently, studies in metazoans have begun to reveal more specialized functions of myosin I. It will be a major challenge in the future to examine the physiological functions of each class I myosin in different cell types of metazoans.     

The search for migraine genes: an overview of current knowledge

Migraine is a complex familial condition that imparts a significant burden on society. There is evidence for a role of genetic factors in migraine, and elucidating the genetic basis of this disabling condition remains the focus of much research. In this review we discuss results of genetic studies to date, from the discovery of the role of neural ion channel gene mutations in familial hemiplegic migraine (FHM) to linkage analyses and candidate gene studies in the more common forms of migraine. The success of FHM regarding discovery of genetic defects associated with the disorder remains elusive in common migraine, and causative genes have not yet been identified. Thus we suggest additional approaches for analysing the genetic basis of this disorder. The continuing search for migraine genes may aid in a greater understanding of the mechanisms that underlie the disorder and potentially lead to significant diagnostic and therapeutic applications. Received 16 December 2005; received after revision 9 October 2006; accepted 13 November 2006     

The Arp2/3 complex: a central regulator of the actin cytoskeleton

In recent years the Arp2/3 complex has emerged as a central regulator of actin dynamics, assembling and cross-linking actin filaments to produce a diverse array of cellular structures. Here I discuss our current state of knowledge about this actin-remodelling machine. The predicted structure of the Arp2/3 complex can be directly correlated with its ability to nucleate, cap and cross-link actin filaments. A growing family of Arp2/3 complex activators such as the WASP family, type I myosins, and the newly identified activators cortactin and Abp1p tightly regulate this activity within the cell. Localised activation of the Arp2/3 complex produces structures such as lamellipodia or actin patches via a process termed dendritic nucleation. Furthermore, several pathogenic microorganisms have evolved strategies to 'hijack' the Arp2/3 complex to their own advantage. Finally, I discuss some of the questions which remain unanswered about this fascinating complex. Received 2 April 2001; received after revision 15 May 2001; accepted 18 May 2001     

Regulation of cytokinesis

At the end of mitosis, daughter cells are separated from each other by cytokinesis. This process involves equal partitioning and segregation of cytoplasm between the two cells. Despite years of study, the mechanism driving cytokinesis in animal cells is not fully understood. Actin and myosin are major components of the contractile ring, the structure at the equator between the dividing cells that provides the force necessary to constrict the cytoplasm. Despite this, there are also tantalizing results suggesting that cytokinesis can occur in the absence of myosin. It is unclear what the roles are of the few other contractile ring components identified to date. While it has been difficult to identify important proteins involved in cytokinesis, it has been even more challenging to pinpoint the regulatory mechanisms that govern this vital process. Cytokinesis must be precisely controlled both spatially and temporally; potential regulators of these parameters are just beginning to be identified. This review discusses the recent progress in our understanding of cytokinesis in animal cells and the mechanisms that may regulate it. Received 24 August 1998; received after revision 9 October 1998; accepted 9 October 1998     

Introduction: molecular and biomechanical basis of osteoarthritis

Osteoarthritis has developed into the most common chronic disease in the highly industrialized nations. Moreover, because of the prevalence of the disease in the elderly, this trend occurs worldwide as a consequence of increasing longevity due to the overall improvement in living conditions and health status. In contrast, research on osteoarthritis is still financially marginalized within biomedical research, so that the molecular and biophysical bases for disease initiation and progression are largely unmapped. The following sequence of five reviews highlights a remarkable change in that body of knowledge taking place at the beginning of the World Health Organization (WHO) 'Bone and Joint Decade 2001-2010'. The data and ideas presented in these articles reflect to some extent the guidelines set up by the WHO and by the National Institutes of Health of the USA and therefore allow a glimpse into the directions that research in osteoarthritis will take in the future.     

Real-time models of morphogenetic processes

Summary Morphological transformations are often describable by simple series kinetic models,AB, ABC, etc., which allow assessment of the rates of interconversion of the distinguishable shapes or forms present and their probabilities of occurrence at various points in time, thus providing a means for kinetic comparisons with biochemical measurements of the molecular-level reactions that cause the transformations. When changes in cell morphology are followed turbidimetrically, the real-time progress curves can be simulated by fitting the data to a form of Beer's law for scattering by mixtures in which the species concentrations change with time in accordance with the chosen kinetic scheme. Because many even relatively large cells are mostly water, classical light scattering theory can be used to interpret the turbidimetric data in terms of simple geometrical models ofaverage cell size and shape suggested by microscopic examination. Two examples are briefly considered, the stimulus-induced changes in blood platelet shape and apparent size and their correlation with cytosolic-free calcium, and apparent swimming motion exhibited by neutrophils in suspension.What do you know about this business? the King said to Alice. Nothing, said Alice. Nothing whatever? persisted the King. Nothing whatever, said Alice. That's very important, the King said. Lewis Carroll (1865), in Alice's Adventures in Wonderland     

The effects of ethanol on embryonic actin: A possible role in teratogenesis

Summary When the neural crest is cultured in the long or short term presence of ethanol, monoclonal anti-actin reveals the development of a disorganized actin cytoskeleton. In the long term, many cells fail to differentiate morphologically, whereas in the short term already differentiated cells rapidly alter their shape and their cell-to-cell contacts.     

Alpha-crystallin: an ATP-independent complete molecular chaperone toward sorbitol dehydrogenase

-Crystallin, the major component of the vertebrate lens, is known to interact with proteins undergoing denaturation and to protect them from aggregation phenomena. Bovine lens sorbitol dehydrogenase (SDH) was previously shown to be completely protected by -crystallin from thermally induced aggregation and inactivation. Here we report that -crystallin, in the presence of the SDH pyridine cofactor NAD(H), can exert a remarkable chaperone action by favoring the recovery of the enzyme activity from chemically denaturated SDH up to 77%. Indeed, even in the absence of the cofactor, -crystallin present at a ratio with SDH of 20:1 (w:w) allows a recovery of 35% of the enzyme activity. The effect of ATP in enhancing -crystallin-promoted SDH renaturation appears to be both nonspecific and to not involve hydrolysis phenomena, thus confirming that the chaperone action of -crystallin is not dependent on ATP as energy donor.Received 28 October 2004; received after revision 22 December 2004; accepted 10 January 2005     

Triplet repeat disorders: discussion of molecular mechanisms

Comparison of the growing number of disorders known to be associated with triplet repeat expansions reveals both common features and a diversity of molecular pathways. Despite significant progress towards the characterization of proteins coded by the mutant genes, the complex nature of these disorders requires identification of all molecular components of the triplet repeat pathways. In this brief review we will discuss recent progress in determining the molecular mechanisms of disorders with unstable trinucleotide mutations. Received 13 January 1999; received after revision 8 March 1999; accepted 9 March 1999     

The molecular basis and clinical aspects of Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is a classic, but not widely known hereditary trait. Its clinical hallmarks are intestinal hamartomatous polyposis and melanin pigmentation of the skin and mucous membranes. In addition, PJS predisposes to cancer . The most common malignancies are small intestinal, colorectal, stomach and pancreatic adenocarcinomas. Other cancer types that probably occur in excess in PJS families include breast and uterine cervical cancer, as well as testicular and ovarian sex cord tumors. The relative risk of cancer may be as high as 18 times that of the general population, and the cancer patients' prognosis is reduced. Recently, the predisposing locus was mapped to 19p13.3 using a novel method. Subsequently, the causative gene was shown to be LKB1 (a.k.a. STK11), a serine/threonine kinase of unknown function. Although preliminary reports seem to suggest a minor role for LKB1 in sporadic tumorigenesis, further investigations are needed. Received 12 October 1998; received after revision 30 November 1998; accepted 30 November 1998     

The origin,diversity, and structure function relationships of insect luciferases

Luciferases are the enzymes that catalyze the reactions that produce light in bioluminescence. Whereas the oxidative mechanism which leads to light emission is similar for most luciferases, these enzymes and their substrates are evolutionarily unrelated. Among all bioluminescent groups, insects constitute one of the most diverse in terms of biochemistry. In the fungus-gnats (Mycetophilidae: Diptera), for example, bioluminescence is generated by two biochemically distinct systems. Despite the diversity, investigations on insect luciferases and biochemistry have been conducted mostly with fireflies. The luciferases from the related phengodid beetles, which can produce green to red bioluminescence using the same chemistry as firefly luciferases, have been recently investigated. Beetle luciferases originated from ancestral acyl-CoA ligases. Present data suggest that conserved motifs among this class of ligases are involved in substrate adenylation. The three-dimensional structure of firefly luciferase was recently solved and mutagenesis studies have been performed identifying putative residues involved in luciferin binding and bioluminescence color determination in several beetle luciferases. The knowledge gained through these studies is helping in the development of useful reporter gene tools for biotechnological and biomedical purposes. Received 4 March 2002; received after revision 13 May 2002; accepted 21 May 2002     

From carrot to clinic: an overview of the retinoic acid signaling pathway

Vitamin A is essential for the formation and maintenance of many body tissues. It is also important for embryonic growth and development and can act as a teratogen at critical periods of development. Retinoic acid (RA) is the biologically active form of vitamin A and its signaling is mediated by the RA and retinoid X receptors. In addition to its role as an important molecule during development, RA has also been implicated in clinical applications, both as a potential anti-tumor agent as well as for the treatment of skin diseases. This review presents an overview of how dietary retinoids are converted to RA, hence presenting the major players in RA metabolism and signaling, and highlights examples of treatment applications of retinoids. Moreover, we discuss the origin and diversification of the retinoid pathway, which are important factors for understanding the evolution of ligand-specificity among retinoid receptors.     

Protein folds: molecular systematics in three dimensions

Advances in methods of structure determination have led to the accumulation of large amounts of protein structural data. Some 500 distinct protein folds have now been characterized, representing one-third of all globular folds that exist. The range of known structural types and the relatively large fraction of the protein universe that has already been sampled have greatly facilitated the discovery of some unifying principles governing protein structure and evolutionary relationships. These include a highly skewed distribution of topological arrangements of secondary-structure elements that favors a few very common connectivities and a highly skewed distribution in the capacity of folds to accommodate unrelated sequences. These and other observations suggest that the number of folds is far fewer than the number of genes, and that the fold universe is dominated by a small number of giant attractors that accommodate large numbers of unrelated sequences. Thus all basic protein folds will likely be determined in the near future, laying the foundation for a comprehensive understanding of the biochemical and cellular functions of whole organisms.     

Review¶Psychrophilic enzymes: molecular basis of cold adaptation

Psychrophilic organisms have successfully colonized polar and alpine regions and are able to grow efficiently at sub-zero temperatures. At the enzymatic level, such organisms have to cope with the reduction of chemical reaction rates induced by low temperatures in order to maintain adequate metabolic fluxes. Thermal compensation in cold-adapted enzymes is reached through improved turnover number and catalytic efficiency. This optimization of the catalytic parameters can originate from a highly flexible structure which provides enhanced abilities to undergo conformational changes during catalysis. Thermal instability of cold-adapted enzymes is therefore regarded as a consequence of their conformational flexibility. A survey of the psychrophilic enzymes studied so far reveals only minor alterations of the primary structure when compared to mesophilic or thermophilic homologues. However, all known structural factors and weak interactions involved in protein stability are either reduced in number or modified in order to increase their flexibility.     

Cellular and molecular aspects of drugs of the future: oxaliplatin

Oxaliplatin (Eloxatine) is a third-generation platinum compound which has shown a wide antitumour effect both in vitro and in vivo, a better safety profile than cisplatin and a lack of cross-resistance with cisplatin and carboplatin. In this scenario, oxaliplatin may represent an innovative and challenging drug extending the antitumour activity in diseases such as gastrointestinal cancer that are not usually sensitive to these coordination complexes. Oxaliplatin has a non-hydrolysable diaminocyclohexane (DACH) carrier ligand which is maintained in the final cytotoxic metabolites of the drug. Like cisplatin, oxaliplatin targets DNA producing mainly 1,2-GG intrastrand cross-links. The cellular and molecular aspects of the mechanism of action of oxaliplatin have not yet been fully elucidated. However, the intrinsic chemical and steric characteristics of the DACH-platinum adducts appear to contribute to the lack of cross-resistance with cisplatin. To date, mismatch repair and replicative bypass appear to be the processes most likely involved in differentiating the molecular responses to these agents. Received 15 March 2002; received after revision 13 May 2002; accepted 21 May 2002 RID="*" ID="*"Corresponding author.