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OPEN ACCESS PLUS
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Contents
14(2): Pp. 97 - 110
Ghita Ghislat and Erwin Knecht
[Open Access Plus] |
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Autophagy and endocytosis are two evolutionarily conserved catabolic processes that comprise vesicle trafficking events for the clearance of the sequestered intracellular and extracellular cargo. Both start differently but end in the same compartment, the lysosome. Mounting evidences from the last years have established the involvement of proteins sensitive to intracellular Ca2+ in the control of the early autophagic steps and in the traffic of autophagic, endocytic and lysosomal vesicles. However, this knowledge is based on dispersed outcomes that do not set up a consensus model of the Ca2+–dependent control of autophagy and endocytosis. Here, we will provide a critical synopsis of insights from the last decade on the involvement of Ca2+–sensor proteins in the activation of autophagy and in fusion events of endocytic vesicles, autophagosomes and lysosomes.
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13(6): Pp. 524 - 546
Michely C. Diniz, Ana Carolina L. Pacheco, Kaio M. Farias and Diana M. de Oliveira
[Open Access Plus] |
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This review will summarize and discuss the current biological understanding of the motile eukaryotic flagellum, as posed out by recent advances enabled by post-genomics and proteomics approaches. The organelle, which is crucial for motility, survival, differentiation, reproduction, division and feeding, among other activities, of many eukaryotes, is a great example of a natural nanomachine assembled mostly by proteins (around 350-650 of them) that have been conserved throughout eukaryotic evolution. Flagellar proteins are discussed in terms of their arrangement on to the axoneme, the canonical “9+2” microtubule pattern, and also motor and sensorial elements that have been detected by recent proteomic analyses in organisms such as Chlamydomonas reinhardtii, sea urchin, and trypanosomatids. Such findings can be remarkably matched up to important discoveries in vertebrate and mammalian types as diverse as sperm cells, ciliated kidney epithelia, respiratory and oviductal cilia, and neuro-epithelia, among others. Here we will focus on some exciting work regarding eukaryotic flagellar proteins, particularly using the flagellar proteome of C. reinhardtii as a reference map for exploring motility in function, dysfunction and pathogenic flagellates. The reference map for the eukaryotic flagellar proteome consists of 652 proteins that include known structural and intraflagellar transport (IFT) proteins, less wellcharacterized signal transduction proteins and flagellar associated proteins (FAPs), besides almost two hundred unannotated conserved proteins, which lately have been the subject of intense investigation and of our present examination.
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13(5): Pp. 467 - 481
Jun Wan, Divya Subramonian and Xiang-Dong Zhang
[Open Access Plus] |
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Posttranslational protein modification by small ubiquitin-related modifier (SUMO) has emerged as an important regulatory mechanism for chromosome segregation during mitosis. This review focuses on how SUMOylation regulates the centromere and kinetochore activities to achieve accurate chromosome segregation during mitosis. Kinetochores are assembled on the specialized chromatin domains called centromeres and serve as the sites for attaching spindle microtubule to segregate sister chromatids to daughter cells. Many proteins associated with mitotic centromeres and kinetochores have been recently found to be modified by SUMO. Although we are still at the early stage of elucidating how SUMOylation controls chromosome segregation during mitosis, a substantial progress has been achieved over the past decade. Furthermore, a major theme that has emerged from the recent studies of SUMOylation in mitosis is that both SUMO conjugation and deconjugation are critical for kinetochore assembly and disassembly. Lastly, we propose a model that SUMOylation coordinates multiple centromere and kinetochore activities to ensure accurate chromosome segregation.
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13(4): Pp. 305 - 330
Leos Shivaya Valasek
[Open Access Plus] |
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Protein synthesis is a fundamental biological mechanism bringing the DNA-encoded genetic information into life by its translation into molecular effectors - proteins. The initiation phase of translation is one of the key points of gene regulation in eukaryotes, playing a role in processes from neuronal function to development. Indeed, the importance of the study of protein synthesis is increasing with the growing list of genetic diseases caused by mutations that affect mRNA translation. To grasp how this regulation is achieved or altered in the latter case, we must first understand the molecular details of all underlying processes of the translational cycle with the main focus put on its initiation. In this review I discuss recent advances in our comprehension of the molecular basis of particular initiation reactions set into the context of how and where individual eIFs bind to the small ribosomal subunit in the pre-initiation complex. I also summarize our current knowledge on how eukaryotic initiation factor eIF3 controls gene expression in the gene-specific manner via reinitiation.
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13(4): Pp. 294 - 304
Xavier Pichon, Lindsay A. Wilson, Mark Stoneley, Amandine Bastide, Helen A King, Joanna Somers and Anne E Willis
[Open Access Plus] |
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A growing body of work demonstrates the importance of post-transcriptional control, in particular translation initiation, in the overall regulation of gene expression. Here we focus on the contribution of regulatory elements within the 5’ and 3’ untranslated regions of mRNA to gene expression in eukaryotic cells including terminal oligopyrimidine tracts, internal ribosome entry segments, upstream open reading frames and cytoplasmic polyadenylation elements. These mRNA regulatory elements may adopt complex secondary structures and/or contain sequence motifs that allow their interaction with a variety of regulatory proteins, RNAs and RNA binding proteins, particularly hnRNPs. The resulting interactions are context-sensitive, and provide cells with a sensitive and fast response to cellular signals such as hormone exposure or cytotoxic stress. Importantly, an increasing number of diseases have been identified, particularly cancers and those associated with neurodegeneration, which originate either from mutation of these regulatory motifs, or from deregulation of their cognate binding partners.
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13(4): Pp. 284 - 293
Ralf-Peter Jansen and Dierk Niessing
[Open Access Plus] |
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At all steps from transcription to translation, RNA-binding proteins play important roles in determining mRNA function. Initially it was believed that for the vast majority of transcripts the role of RNA-binding proteins is limited to general functions such as splicing and translation. However, work from recent years showed that members of this class of proteins also recognize several mRNAs via cis-acting elements for their incorporation into large motor-containing particles. These particles are transported to distant subcellular sites, where they become subsequently translated. This process, called mRNA localization, occurs along microtubules or actin filaments, and involves kinesins, dyneins, as well as myosins. Although mRNA localization has been detected in a large number of organisms from fungi to humans, the underlying molecular machineries are not well understood. In this review we will outline general principles of mRNA localization and highlight three examples, for which a comparably large body of information is available. The first example is She2p/She3p-dependent localization of ASH1 mRNA in budding yeast. It is particularly well suited to highlight the interdependence between different steps of mRNA localization. The second example is Staufen-dependent localization of oskar mRNA in the Drosophila embryo, for which the importance of nuclear events for cytoplasmic localization and translational control has been clearly demonstrated. The third example summarizes Egalitarian/Bicaudal D-dependent mRNA transport events in the oocyte and embryo of Drosophila. We will highlight general themes and differences, point to similarities in other model systems, and raise open questions that might be answered in the coming years.
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13(3): Pp. 267 - 279
Walter Hohlweg, Simone Kosol and Klaus Zangger
[Open Access Plus] |
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Many naturally occurring bioactive peptides bind to biological membranes. Studying and elucidating the mode of interaction is often an essential step to understand their molecular and biological functions. To obtain the complete orientation and immersion depth of such compounds in the membrane or a membrane-mimetic system, a number of methods are available, which are separated in this review into four main classes: solution NMR, solid-state NMR, EPR and other methods. Solution NMR methods include the Nuclear Overhauser Effect (NOE) between peptide and membrane signals, residual dipolar couplings and the use of paramagnetic probes, either within the membrane-mimetic or in the solvent. The vast array of solid state NMR methods to study membrane-bound peptide orientation and localization includes the anisotropic chemical shift, PISA wheels, dipolar waves, the GALA, MAOS and REDOR methods and again the use of paramagnetic additives on relaxation rates. Paramagnetic additives, with their effect on spectral linewidths, have also been used in EPR spectroscopy. Additionally, the orientation of a peptide within a membrane can be obtained by the anisotropic hyperfine tensor of a rigidly attached nitroxide label. Besides these magnetic resonance techniques a series of other methods to probe the orientation of peptides in membranes has been developed, consisting of fluorescence-, infrared- and oriented circular dichroism spectroscopy, colorimetry, interface-sensitive X-ray and neutron scattering and Quartz crystal microbalance.
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13(2): Pp. 180 - 191
Edgardo J. Toro, David A. Ostrov, Thomas J. Wronski and L. Shannon Holliday
[Open Access Plus] |
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Binding between vacuolar H+-ATPases (V-ATPases) and microfilaments is mediated by an actin binding domain in the B-subunit. Both isoforms of mammalian B-subunit bind microfilaments with high affinity. A similar actinbinding activity has been demonstrated in the B-subunit of yeast. A conserved “profilin-like” domain in the B-subunit mediates this actin-binding activity, named due to its sequence and structural similarity to an actin-binding surface of the canonical actin binding protein profilin. Subtle mutations in the “profilin-like” domain eliminate actin binding activity without disrupting the ability of the altered protein to associate with the other subunits of V-ATPase to form a functional proton pump. Analysis of these mutated B-subunits suggests that the actin-binding activity is not required for the “housekeeping” functions of V-ATPases, but is important for certain specialized roles. In osteoclasts, the actin-binding activity is required for transport of V-ATPases to the plasma membrane, a prerequisite for bone resorption. A virtual screen led to the identification of enoxacin as a small molecule that bound to the actin-binding surface of the B2-subunit and competitively inhibited B2-subunit and actin interaction. Enoxacin disrupted osteoclastic bone resorption in vitro, but did not affect osteoblast formation or mineralization. Recently, enoxacin was identified as an inhibitor of the virulence of Candida albicans and more importantly of cancer growth and metastasis. Efforts are underway to determine the mechanisms by which enoxacin and other small molecule inhibitors of B2 and microfilament binding interaction selectively block bone resorption, the virulence of Candida, cancer growth, and metastasis.
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11(6): Pp. 471 - 484
Ivan Stamenkovic and Qin Yu
[Open Access Plus] |
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Genetic alterations of neurofibromatosis type 2 (NF2) gene lead to the development of schwannomas, meningiomas, and ependymomas. Mutations of NF2 gene were also found in thyroid cancer, mesothelioma, and melanoma, suggesting that it functions as a tumor suppressor in a wide spectrum of cells. The product of NF2 gene is merlin (moesinezrin- radixin-like protein), a member of the Band 4.1 superfamily proteins. Merlin shares significant sequence homology with the ERM (Ezrin-Radixin-Moesin) family proteins and serves as a linker between transmembrane proteins and the actin- cytoskeleton. Merlin is a multifunctional protein and involved in integrating and regulating the extracellular cues and intracellular signaling pathways that control cell fate, shape, proliferation, survival, and motility. Recent studies showed that merlin regulates the cell-cell and cell-matrix adhesions and functions of the cell surface adhesion/extracellular matrix receptors including CD44 and that merlin and CD44 antagonize each others function and work upstream of the mammalian Hippo signaling pathway. Furthermore, merlin plays important roles in stabilizing the contact inhibition of proliferation and in regulating activities of several receptor tyrosine kinases. Accumulating data also suggested an emerging role of merlin as a negative regulator of growth and progression of several non-NF2 associated cancer types. Together, these recent advances have improved our basic understanding about merlin function, its regulation, and the major signaling pathways regulated by merlin and provided the foundation for future translation of these findings into the clinic for patients bearing the cancers in which merlin function and/or its downstream signaling pathways are impaired or altered.
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10(4): Pp. 339 - 359
Oyvind Halskau, Arturo Muga and Aurora Martinez
[Open Access Plus] |
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Amphitrophic proteins are soluble, globular proteins that may - under certain conditions - interact reversibly with a plasma membrane. How this apparent duality in the properties of a protein is achieved has been a relatively littlestudied subject until recently. In this review we aim to summarize the current knowledge regarding some important amphitrophic systems in which the interaction with the membrane does not require post-translational functional groups, but is an intrinsic property of the protein. We discuss mechanisms and driving forces involved in membrane binding in the context of two related concepts in protein folding and function that appear to have implications for understanding the association of proteins with membranes; first, the existence of some proteins with low-energy barrier heights for protein folding. Low folding barriers and the ability of proteins to form stable molten globule states are rationales that can explain how a protein can gain access to an ensemble (or continuum) of non-native conformations that are competent membrane binders. Second, the focus on order-disorder and disorder-order transitions to explain protein function, a concept which has been mainly developed within the novel protein trinity paradigm. Here, protein function can arise from any of three thermodynamic states: a solid, crystal-like state; a dense fluid state; and an extended disordered state. Together these concepts aid to understand amphitrophic mechanism and to unify interpretations of protein behaviour with respect to the degree of (un)unfolding of the membrane-bound proteins.
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9(4): Pp. 394 - 406
Sjoerd J. de Vries and Alexandre M.J.J. Bonvin
[Open Access Plus] |
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Protein-protein interface prediction is a booming field, with a substantial growth in the number of new methods being published the last two years. The increasing number of available three-dimensional structures of protein-protein complexes has enabled large-scale statistical analyses of protein interfaces, considering evolutionary, physicochemical and structural properties. Successful combinations of these properties have led to more accurate interface predictors in recent years. In addition to parametric combination, machine learning algorithms have become popular. In the meantime, assessing the absolute and relative performance of interface predictors remains very difficult: This is due to differences in both the output of the various interface predictors, and in the evaluation criteria used by their respective authors. This review provides an overview of the state of the art in the field, and discusses the performance of existing interface predictors. The focus is mainly on protein-protein interface prediction, although most issues are also valid for other kinds of interface prediction.
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9(3): Pp. 260 - 274
Mark T. Oakley, Daniel Barthel, Yuri Bykov, Jonathan M. Garibaldi, Edmund K. Burke, Natalio Krasnogor and Jonathan D. Hirst
[Open Access Plus] |
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Optimisation problems pervade structural bioinformatics. In this review, we describe recent work addressing a selection of bioinformatics challenges. We begin with a discussion of research into protein structure comparison, and highlight the utility of Kolmogorov complexity as a measure of structural similarity. We then turn to research into de novo protein structure prediction, in which structures are generated from first principles. In this endeavour, there is a compromise between the detail of the model and the extent to which the conformational space of the protein can be sampled. We discuss some developments in this area, including off-lattice structure prediction using the great deluge algorithm. One strategy to reduce the size of the search space is to restrict the protein chain to sites on a regular lattice. In this context, we highlight the use of memetic algorithms, which combine genetic algorithms with local optimisation, to the study of simple protein models on the two-dimensional square lattice and the face-centred cubic lattice.
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8(5): Pp. 484 - 495
M. A. Wouters, R. A. George and N. L. Haworth
[Open Access Plus] |
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Seminal studies by Richardson [1] and Thornton [2] defined the constraints imposed by protein structure on disulfide formation and flagged forbidden regions of primary or secondary structure seemingly incapable of forming disulfide bonds between resident cysteine pairs. With respect to secondary structure, disulfide bonds were not found between cysteine pairs: A. on adjacent β-stands [1]; B. in a single helix or strand [2]; C. on non-adjacent strands of the same β-sheet [2]. In primary structure, disulfide bonds were not found between cysteine pairs: D. adjacent in the sequence [2]. In the intervening years it has become apparent that all these forbidden regions are indeed occupied by disulfide-bonded cysteines, albeit rather strained ones. It has been observed that sources of strain in a protein structure, such as residues in forbidden regions of the Ramachandran plot and cis-peptide bonds, are found in functionally important regions of the protein and warrant further investigation [3-5]. Like the Ramachandran plot, the earlier studies by Richardson [1] and Thornton [2] have identified a fundamental truth in protein stereochemistry: “forbidden” disulfides adopt strained conformations, but there is likely a functional reason for this. Emerging evidence supports a role for forbidden disulfides in redoxregulation of proteins.
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