Trends in biochemical sciences

PCSK9 and LDL cholesterol: unravelling the target to design the bullet.

Publication Date: 2008 Jul 29 PMID: 18672372
Authors: Costet, P. - Krempf, M. - Cariou, B.
Journal: Trends Biochem Sci

Gain-of-function mutations within proprotein convertase subtilisin kexin type 9 (PCSK9) are linked to familial autosomal dominant hypercholesterolaemia, a disease characterized by elevated plasma concentrations of cholesterol associated with low-density lipoproteins (LDLs). Conversely, PCSK9 loss-of-function mutations result in low levels of LDL cholesterol (LDLC) and protect against coronary heart disease. Although compelling evidence indicates that PCSK9 impairs the LDLR pathway, its role in cholesterol metabolism remains incompletely defined. In the past two years, several new biochemical findings, including the PCSK9 crystal structure and the identification of several transcriptional repressors, were reported. Moreover, new clinical and epidemiological data have revealed the correlation between plasma PCSK9 concentrations and LDLC levels.

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Grasping molecular structures through publication-integrated 3D models.

Publication Date: 2008 Jul 29 PMID: 18672371
Authors: Kumar, P. - Ziegler, A. - Ziegler, J. - Uchanska-Ziegler, B. - Ziegler, A.
Journal: Trends Biochem Sci

Although the need for communicating 3D data using simple and intuitive means extends to disciplines as diverse as biology, engineering sciences and the visual arts, none of the currently available molecular-visualization programs depicting potentially highly complex structures are compatible with the portable document format (PDF), the current gold standard of electronic publishing. Therefore, it is highly desirable for authors to be able to provide their readers with a basic 3D display of structures that can be accessed without the need for specialized visualization software. Here, we describe how an interactive 3D model of a molecular complex can be embedded directly into a PDF, thus providing readers with important and educational visual information that would otherwise be more difficult to disseminate.

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Arrangements in the modular evolution of proteins.

Publication Date: 2008 Jul 23 PMID: 18656364
Authors: Moore, A. D. - Bjorklund, A. K. - Ekman, D. - Bornberg-Bauer, E. - Elofsson, A.
Journal: Trends Biochem Sci

It has been known for the last couple of decades that proteins evolve partly through rearrangements of larger fragments, typically domains. These units are considered the basic modules of protein structure, evolution and function. In the last few years, the analysis of protein-domain rearrangements has provided us with functional and evolutionary insights and has aided improved functional predictions and domain assignments to previously uncharacterised genes and proteins. Although some mechanisms that govern modular rearrangements of protein domains have been uncovered, such as the addition or deletion of a single N- or C-terminal domain, much is still unknown about the genetics behind these arrangements.

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The insulin receptor: a prototype for dimeric, allosteric membrane receptors?

Publication Date: 2008 Aug PMID: 18640841
Authors: De Meyts, P.
Journal: Trends Biochem Sci

The recent crystallographic structure of the insulin receptor (IR) extracellular domain has brought us closer to ending several decades of speculation regarding the stoichiometry and mechanism of insulin-receptor binding and negative cooperativity. It supports a bivalent crosslinking model whereby two sites on the insulin molecule alternately crosslink two partial-binding sites on each insulin-receptor half. Ligand-induced or -stabilized receptor dimerization or oligomerization is a general feature of receptor tyrosine kinases (RTKs), in addition to cytokine receptors, but the kinetic consequences of this mechanism have been less well studied in other RTKs than in the IR. Surprisingly, recent studies indicate that constitutive dimerization and negative cooperativity are also ubiquitous properties of G-protein-coupled receptors (GPCRs), which show allosteric mechanisms similar to those described for the IR.

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UnPAKing the class differences among p21-activated kinases.

Publication Date: 2008 Aug PMID: 18639460
Authors: Eswaran, J. - Soundararajan, M. - Kumar, R. - Knapp, S.
Journal: Trends Biochem Sci

The p21-activated kinases (PAKs) are signal transducers, central to many vital cellular processes, including cell morphology, motility, survival, gene transcription and hormone signalling. The mammalian PAK family contains six serine/threonine kinases divided into two subgroups, group I (PAK 1-3) and group II (PAK4-6), based on their domain architecture and regulation. PAKs functioning as dynamic signalling nodes present themselves as attractive therapeutic targets in tumours, neurological diseases and infection. The recent findings across all PAKs, including newly reported structures, shed light on the cellular functions of PAKs, highlighting molecular mechanisms of activation, catalysis and substrate specificity. We believe that a comprehensive understanding of the entire PAK family is essential for developing strategies towards PAK-targeted therapeutics.

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Necrotic cell death and 'necrostatins': now we can control cellular explosion.

Publication Date: 2008 Aug PMID: 18635359
Authors: Vandenabeele, P. - Declercq, W. - Berghe, T. V.
Journal: Trends Biochem Sci

The receptor-interacting protein 1 (RIP1) kinase activity is necessary for death-receptor-induced necrotic cell death. Recently, it has been demonstrated that 'necrostatins' efficiently block tumor necrosis factor-induced necrotic cell death through the inhibition of RIP1 kinase activity. This discovery supports the concept that receptor-induced necrosis, just like apoptosis, is a controlled cellular process. In addition, necrostatins are becoming important tools for evaluating the contribution of necrotic cell death in experimental disease models.

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Alternative splicing resulting in nonsense-mediated mRNA decay: what is the meaning of nonsense?

Publication Date: 2008 Aug PMID: 18621535
Authors: McGlincy, N. J. - Smith, C. W.
Journal: Trends Biochem Sci

Alternative splicing (AS) strongly affects gene expression by generating protein isoform diversity. However, up to one-third of human AS events create a premature termination codon that would cause the resulting mRNA to be degraded by nonsense-mediated mRNA decay (NMD). The extent to which such events represent functionally selected post-transcriptional gene control, as opposed to noise in the splicing process, has been a contentious issue. Recent analyses indicate that many splicing regulatory proteins are themselves regulated by AS-NMD. Intriguingly, many of these AS-NMD events are coincident with ultraconserved genomic elements, which indicates their importance to vertebrate biology. Examination of these highly conserved events has led to new insights into the functions of AS-NMD and the role it can have in physiological circumstances.

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New roles for pyruvate kinase M2: working out the Warburg effect.

Publication Date: 2008 Aug PMID: 18603432
Authors: Ferguson, E. C. - Rathmell, J. C.
Journal: Trends Biochem Sci

The origins and role of the Warburg effect have remained uncertain for many years. Two recent studies demonstrate that an embryonic- and cancer-cell-specific isoform of the enzyme pyruvate kinase M2 (PKM2) is regulated by binding to phospho-tyrosine motifs and promotes increased cell growth and tumor development. PKM2 enhances the use of glycolytic intermediates for macromolecular biosynthesis and tumor growth. These findings illustrate the distinct advantages of this metabolic phenotype in cancer cell growth.

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Zinc-finger UBPs: regulators of deubiquitylation.

Publication Date: 2008 Aug PMID: 18603431
Authors: Bonnet, J. - Romier, C. - Tora, L. - Devys, D.
Journal: Trends Biochem Sci

Deubiquitylating enzymes have key regulatory roles in multiple cellular processes by mediating ubiquitin removal and processing. The ubiquitin-specific processing proteases (USPs) represent the largest subclass of deubiquitylases. Recently, several USPs that recognize the monoubiquitylated histones H2A and/or H2B have been identified. Among these enzymes, three USPs contain a zinc-finger ubiquitin-specific protease (ZnF-UBP) domain, indicating that this domain plays a crucial part in regulating their activity. To address the putative function of this domain, we systematically analysed and aligned yeast and human ZnF-UBP-containing proteins. By complementing our analysis with structural and functional data, we present a classification of the different ZnF-UBP-containing proteins and a model for their regulation.

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Non-functional phosphorylations?

Publication Date: 2008 Aug PMID: 18603430
Authors: Lienhard, G. E.
Journal: Trends Biochem Sci

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Protease-catalysed protein splicing: a new post-translational modification?

Publication Date: 2008 Aug PMID: 18599295
Authors: Saska, I. - Craik, D. J.
Journal: Trends Biochem Sci

In all organisms, proteases catalyse peptide-bond hydrolysis and mediate protein function for a multitude of cellular processes. Mechanistically, nothing prevents proteases from also catalysing peptide-bond ligation; however, this 'reverse' reaction rarely is observed. In eukaryotes its presence has been viewed as an anomaly. Recent studies from plants and animals now challenge this assumption, indicating that protease-catalysed protein splicing is a bona fide post-translational modification. Increasing evidence indicates that the proximity of protein substrates, imposed either by their structure or by the physical constraints of the local environment, dictates when the splicing reaction will occur. This previously under-recognized splicing mechanism could increase intracellular protein diversity, thereby expanding the size of the proteome and sequence diversity beyond the predictions from genomic studies.

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Akt signaling: a damaging interaction makes good.

Publication Date: 2008 Aug PMID: 18585043
Authors: Toker, A.
Journal: Trends Biochem Sci

Phosphorylation of the protein kinase Akt at Ser473 is a key regulatory event in the induction of cellular survival mechanisms. A new study provides a novel mechanism for Akt activation. In cells and mice exposed to DNA-damaging insults, Ser473 phosphorylation is mediated by the DNA-dependent protein kinase at sites of DNA double-strand breaks. This event triggers the induction of a transcriptional program that promotes survival in response to DNA damage.

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