Trends in biochemical sciences

Emerging complex pathways of the actomyosin powerstroke.

Publication Date: 2010 Aug 26 PMID: 20801044
Authors: Malnasi-Csizmadia, A. - Kovacs, M.
Journal: Trends Biochem Sci

Actomyosin powers muscle contraction and various cellular activities, including cell division, differentiation, intracellular transport and sensory functions. Despite their crucial roles, key aspects of force generation have remained elusive. To perform efficient force generation, the powerstroke must occur while myosin is bound to actin. Paradoxically, this process must be initiated when myosin is in a very low actin-affinity state. Recent results shed light on a kinetic pathway selection mechanism whereby the actin-induced activation of the swing of myosin's lever enables efficient mechanical functioning. Structural elements and biochemical principles involved in this mechanism are conserved among various NTPase-effector (e.g. kinesin-microtubule, G protein exchange factor and kinase-scaffold protein) systems that perform chemomechanical or signal transduction.

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Cooperative and uncooperative cyclic-nucleotide-gated ion channels.

Publication Date: 2010 Aug 20 PMID: 20729090
Authors: Cukkemane, A. - Seifert, R. - Kaupp, U. B.
Journal: Trends Biochem Sci

Ion channels gated by cyclic nucleotides serve multiple functions in sensory signaling in diverse cell types ranging from neurons to sperm. Newly discovered members from bacteria and marine invertebrates provide a wealth of structural and functional information on this channel family. A hallmark of classical tetrameric cyclic-nucleotide-gated channels is their cooperative activation by binding of several ligands. By contrast, the new members seem to be uncooperative, and binding of a single ligand molecule suffices to open these channels. These new findings provide a fresh look at the mechanism of allosteric activation of ion channels.

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Chromatin regulation and genome maintenance by mammalian SIRT6.

Publication Date: 2010 Aug 20 PMID: 20729089
Authors: Tennen, R. I. - Chua, K. F.
Journal: Trends Biochem Sci

Saccharomyces cerevisiae Sir2 is an NAD(+)-dependent histone deacetylase that links chromatin silencing to genomic stability, cellular metabolism and lifespan regulation. In mice, deficiency for the Sir2 family member SIRT6 leads to genomic instability, metabolic defects and degenerative pathologies associated with aging. Until recently, SIRT6 was an orphan enzyme whose catalytic activity and substrates were unclear. However, new mechanistic insights have come from the discovery that SIRT6 is a highly substrate-specific histone deacetylase that promotes proper chromatin function in several physiologic contexts, including telomere and genome stabilization, gene expression and DNA repair. By maintaining both the integrity and the expression of the mammalian genome, SIRT6 thus serves several roles that parallel Sir2 function. In this article, we review recent advances in understanding the mechanisms of SIRT6 action and their implications for human biology and disease.

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Regulation of autophagy by ROS: physiology and pathology.

Publication Date: 2010 Aug 19 PMID: 20728362
Authors: Scherz-Shouval, R. - Elazar, Z.
Journal: Trends Biochem Sci

Reactive oxygen species (ROS) are small and highly reactive molecules that can oxidize proteins, lipids and DNA. When tightly controlled, ROS serve as signaling molecules by modulating the activity of the oxidized targets. Accumulating data point to an essential role for ROS in the activation of autophagy. Be the outcome of autophagy survival or death and the initiation conditions starvation, pathogens or death receptors, ROS are invariably involved. The nature of this involvement, however, remains unclear. Moreover, although connections between ROS and autophagy are observed in diverse pathological conditions, the mode of activation of autophagy and its potential protective role remain incompletely understood. Notably, recent advances in the field of redox regulation of autophagy focus on the role of mitochondria as a source of ROS and on mitophagy as a means for clearance of ROS.

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Response to Corcos: exceptions to the rules.

Publication Date: 2010 Aug 19 PMID: 20728361
Authors: Feige, M. J. - Hendershot, L. M. - Buchner, J.
Journal: Trends Biochem Sci

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Immunoglobulin transport in the absence of light chains.

Publication Date: 2010 Aug 19 PMID: 20728360
Authors: Corcos, D.
Journal: Trends Biochem Sci

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Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases.

Publication Date: 2010 Aug 19 PMID: 20728359
Authors: Loenarz, C. - Schofield, C. J.
Journal: Trends Biochem Sci

Pioneering work in the 1960s defined prolyl and lysyl hydroxylations as physiologically important oxygenase-catalyzed modifications in collagen biosynthesis; subsequent studies demonstrated that extracellular epidermal growth factor-like domains were hydroxylated at aspartyl and asparaginyl residues. More recent work on the hypoxia-sensing mechanism in animals has shown that prolyl and asparaginyl hydroxylation of the hypoxia-inducible transcription factor play central roles in sensing hypoxia, by regulating protein-protein interactions in an oxygen-dependent manner. The collective results imply that protein hydroxylation is more common than previously perceived. Most protein hydroxylases employ Fe(II) as a cofactor, and 2-oxoglutarate and oxygen as co-substrates. Related enzymes catalyze the demethylation of N(varepsilon)-methyl lysine residues in histones and of N-methylated nucleic acids, as well as hydroxylation of 5-methyl cytosine in DNA and 5-methoxycarbonylmethyluridine at the wobble position of tRNA. The combination of new molecular biological and analytical techniques is likely to reveal further roles for oxygenase-mediated modifications to biomacromolecules.

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Cellular strategies for the assembly of molecular machines.

Publication Date: 2010 Aug 18 PMID: 20727772
Authors: Chari, A. - Fischer, U.
Journal: Trends Biochem Sci

Molecular machines are supramolecular assemblies of biomolecules (proteins, RNA and/or DNA) that facilitate a diversity of biological tasks in the cells of all organisms. How these complex structures are built within the crowded cellular environment is, therefore, a central question in the biological sciences. Recent studies on spliceosomal uridine-rich small nuclear ribonucleoproteins (snRNPs) have unveiled cellular assembly strategies for RNA-protein complexes. snRNPs form in vivo by the coordinated action of an elaborate assembly line consisting of assembly chaperones, scaffolding proteins and catalysts. These newly discovered strategies exhibit similarities to those employed by protein complexes such as ribulose-1,5-bisphosphate-carboxylase (Rubisco) and allow the elucidation of general rules for how molecular machines are formed in vivo.

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Influence of solubilizing environments on membrane protein structures.

Publication Date: 2010 Aug 17 PMID: 20724162
Authors: Cross, T. A. - Sharma, M. - Yi, M. - Zhou, H. X.
Journal: Trends Biochem Sci

Membrane protein structures are stabilized by weak interactions and are influenced by additional interactions with the solubilizing environment. Structures of influenza virus A M2 protein, a proven drug target, have been determined in three different environments, thus providing a unique opportunity to assess environmental influences. Structures determined in detergents and detergent micelles can have notable differences from those determined in lipid bilayers. These differences make it imperative to validate membrane protein structures.

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Nuclear export of mRNA.

Publication Date: 2010 Aug 16 PMID: 20719516
Authors: Stewart, M.
Journal: Trends Biochem Sci

The nuclear export of mRNA, in which Mex67-Mtr2 mediates movement of mature transcripts through nuclear pores, represents the culmination of the nuclear portion of the gene expression pathway. Nuclear export is closely integrated with transcription and processing, and is based on forming a messenger ribonucleoprotein (mRNP) export complex in the nucleus that is able to diffuse back and forth through the pores. Directionality is imposed by remodelling of the mRNP in the cytoplasm, thereby removing key transport-related proteins and preventing its return to the nucleus. The nuclear and cytoplasmic steps of this pathway, in which Mex67-Mtr2 and Nab2 are added and removed, are crucial, and both involve remodelling of the mRNP, which is mediated by DEAD-box helicases together with adaptor and accessory proteins. Recent structural and cell biology results provide key information that should enable development of a detailed understanding of this central cellular process at a molecular level.

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The 3D structures of VDAC represent a native conformation.

Publication Date: 2010 Aug 11 PMID: 20708406
Authors: Hiller, S. - Abramson, J. - Mannella, C. - Wagner, G. - Zeth, K.
Journal: Trends Biochem Sci

The most abundant protein of the mitochondrial outer membrane is the voltage-dependent anion channel (VDAC), which facilitates the exchange of ions and molecules between mitochondria and cytosol and is regulated by interactions with other proteins and small molecules. VDAC has been studied extensively for more than three decades, and last year three independent investigations revealed a structure of VDAC-1 exhibiting 19 transmembrane beta-strands, constituting a unique structural class of beta-barrel membrane proteins. Here, we provide a historical perspective on VDAC research and give an overview of the experimental design used to obtain these structures. Furthermore, we validate the protein refolding approach and summarize the biochemical and biophysical evidence that links the 19-stranded structure to the native form of VDAC.

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