Molecular Principles of Gene Fusion Mediated Rewiring of Protein Interaction Networks in Cancer

Gene fusions are common cancer-causing mutations, but the molecular principles by which fusion protein products affect interaction networks and cause disease are not well understood. Here, we perform an integrative analysis of the structural, interactomic, and regulatory properties of thousands of putative fusion proteins. We demonstrate that genes that form fusions (i.e., parent genes) tend to be highly connected hub genes, whose protein products are enriched in structured and disordered interaction-mediating features. Fusion often results in the loss of these parental features and the depletion of regulatory sites such as post-translational modifications. Fusion products disproportionately connect proteins that did not previously interact in the protein interaction network. In this manner, fusion products can escape cellular regulation and constitutively rewire protein interaction networks. We suggest that the deregulation of central, interaction-prone proteins may represent a widespread mechanism by which fusion proteins alter the topology of cellular signaling pathways and promote cancer. Paper by Natasha Latysheva et al can be found here.

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Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region

Class A G-protein-coupled receptors (GPCRs) are a large family of membrane proteins that mediate a wide variety of physiological functions, including vision, neurotransmission and immune responses. They are the targets of nearly one-third of all prescribed medicinal drugs such as beta blockers and antipsychotics. GPCR activation is facilitated by extracellular ligands and leads to the recruitment of intracellular G proteins. Structural rearrangements of residue contacts in the transmembrane domain serve as ‘activation pathways’ that connect the ligand-binding pocket to the G-protein-coupling region within the receptor. In order to investigate the similarities in activation pathways across class A GPCRs, we analysed 27 GPCRs from diverse subgroups for which structures of active, inactive or both states were available. Here we show that, despite the diversity in activation pathways between receptors, the pathways converge near the G-protein-coupling region. This convergence is mediated by a highly conserved structural rearrangement of residue contacts between transmembrane helices 3, 6 and 7 that releases G-protein-contacting residues. The convergence of activation pathways may explain how the activation steps initiated by diverse ligands enable GPCRs to bind a common repertoire of G proteins. Paper by AJ Venkatakrishnan et al can be found here.

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Conserved Sequence Preferences Contribute to Substrate Recognition by the Proteasome

The proteasome has pronounced preferences for the amino acid sequence of its substrates at the site where it initiates degradation. Here, we report that modulating these sequences can tune the steady-state abundance of proteins over 2 orders of magnitude in cells. This is the same dynamic range as seen for inducing ubiquitination through a classic N-end rule degron. The stability and abundance of His3 constructs dictated by the initiation site affect survival of yeast cells and show that variation in proteasomal initiation can affect fitness. The proteasome’s sequence preferences are linked directly to the affinity of the initiation sites to their receptor on the proteasome and are conserved between Saccharomyces cerevisiae, Schizosaccharomyces pombe, and human cells. These findings establish that the sequence composition of unstructured initiation sites influences protein abundance in vivo in an evolutionarily conserved manner and can affect phenotype and fitness. Paper by Yu H et al can be found here.

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M. Madan Babu has been elected as a member of the European Molecular Biology Organisation (EMBO)

EMBO elects new members annually on the basis of scientific excellence and outstanding research contributions. The organisation promotes excellence in life sciences by supporting talented researchers, and stimulating exchange of scientific information. Madan, along with 57 other researchers, joins more than 1700 of the best researchers from Europe and around the world. Please see here for the EMBO and here for the LMB press release.

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Discovering and understanding oncogenic gene fusions through data intensive computational approaches.

Although gene fusions have been recognized as important drivers of cancer for decades, our understanding of the prevalence and function of gene fusions has been revolutionized by the rise of next-generation sequencing, advances in bioinformatics theory and an increasing capacity for large-scale computational biology. The computational work on gene fusions has been vastly diverse, and the present state of the literature is fragmented. It will be fruitful to merge three camps of gene fusion bioinformatics that appear to rarely cross over: (i) data-intensive computational work characterizing the molecular biology of gene fusions; (ii) development research on fusion detection tools, candidate fusion prioritization algorithms and dedicated fusion databases and (iii) clinical research that seeks to either therapeutically target fusion transcripts and proteins or leverages advances in detection tools to perform large-scale surveys of gene fusion landscapes in specific cancer types. In this review, we unify these different-yet highly complementary and symbiotic-approaches with the view that increased synergy will catalyze advancements in gene fusion identification, characterization and significance evaluation. Paper by Natasha Latysheva and M. Madan Babu can be found here.

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Welcome to Dr Mark Bayfield!

Dr Mark Bayfield is a sabbatical visitor from Dept of Biology, York University, Toronto and has joined our group for 5 months to learn techniques in computational biology (data integration and analysis of next generation sequencing data).

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Welcome to Dr Andal Murthy!

Welcome to Andal who has just started as a postdoc in our group.

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Affinity and competition for TBP are molecular determinants of gene expression noise

Cell-to-cell variation in gene expression levels (noise) generates phenotypic diversity and is an important phenomenon in evolution, development and disease. TATA-box binding protein (TBP) is an essential factor that is required at virtually every eukaryotic promoter to initiate transcription. While the presence of a TATA-box motif in the promoter has been strongly linked with noise, the molecular mechanism driving this relationship is less well understood. Through an integrated analysis of multiple large-scale data sets, computer simulation and experimental validation in yeast, we provide molecular insights into how noise arises as an emergent property of variable binding affinity of TBP for different promoter sequences, competition between interaction partners to bind the same surface on TBP (to either promote or disrupt transcription initiation) and variable residence times of TBP complexes at a promoter. These determinants may be fine-tuned under different conditions and during evolution to modulate eukaryotic gene expression noise. Paper by Charles Ravarani et al can be found here.

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Rita Pancsa is a Fellow of Darwin College

Congratulations to our postdoc Rita to be elected as a Fellow of Darwin College!

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Tilman Flock is awarded the Max Perutz Student Prize 2015

Big congratulations to Tilman to win this year’s Max Perutz Student Prize.

The Max Perutz Student Prize is awarded annually for outstanding work performed at the LMB prior to the award of a PhD. The 2015 prize has been awarded to Tilman Flock, for his comprehensive computational analysis of GTP-binding proteins (G proteins), revealing the universal nature of their interactions and activation.

Tilman, a third year PhD student in the group of Madan Babu in the Structural Studies Division, undertook a systematic analysis of over 80 structures and 950 sequences of G proteins from different species to reveal how the core mechanism of activation and recognition is conserved, even while new specific interactions evolve. In humans there are over 800 G protein-coupled receptors which, upon binding of an extracellular ligand, activate one or more of 16 different G proteins by triggering the exchange of GDP for GTP, thus initiating a series of signalling pathways. It is these receptors that allow us to smell different chemicals, respond to adrenalin, and sense neurotransmitters in the brain, amongst many other functions. More than 30% of all prescribed small molecule drugs act by stimulating or inhibiting them. Since the 1980’s, there have been over 11,000 publications relating to how G proteins work. Tilman’s elegant methodological approach unifies a vast amount of data, providing a framework for the whole field. It is a general approach that can be extended to other proteins, and it shows the power of large-scale analysis of the ever-growing mass of published data.

See Flock et al, Nature 524, 173-179 (2015).

The research student prize is awarded by the Max Perutz Fund. The Fund was established for the promotion and advancement of education and research in molecular biology and allied biomedical sciences.

Photo and text are taken from the LMB website.

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