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M Madan Babu

Natasha S Latysheva, Matt E Oates, Louis Maddox, Tilman Flock, Julian Gough, Marija Buljan, Robert J Weatheritt, M Madan Babu
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...
August 18, 2016: Molecular Cell
A J Venkatakrishnan, Xavier Deupi, Guillaume Lebon, Franziska M Heydenreich, Tilman Flock, Tamara Miljus, Santhanam Balaji, Michel Bouvier, Dmitry B Veprintsev, Christopher G Tate, Gebhard F X Schertler, M Madan Babu
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...
August 25, 2016: Nature
Houqing Yu, Amit K Singh Gautam, Shameika R Wilmington, Dennis Wylie, Kirby Martinez-Fonts, Grace Kago, Marie Warburton, Sreenivas Chavali, Tomonao Inobe, Ilya J Finkelstein, M Madan Babu, Andreas Matouschek
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...
July 8, 2016: Journal of Biological Chemistry
Natasha S Latysheva, M Madan Babu
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...
June 2, 2016: Nucleic Acids Research
Charles N J Ravarani, Guilhem Chalancon, Michal Breker, Natalia Sanchez de Groot, M Madan Babu
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...
2016: Nature Communications
Dawei Sun, Tilman Flock, Xavier Deupi, Shoji Maeda, Milos Matkovic, Sandro Mendieta, Daniel Mayer, Roger J P Dawson, Gebhard F X Schertler, M Madan Babu, Dmitry B Veprintsev
We present comprehensive maps at single-amino acid resolution of the residues stabilizing the human Gαi1 subunit in nucleotide- and receptor-bound states. We generated these maps by measuring the effects of alanine mutations on the stability of Gαi1 and the rhodopsin-Gαi1 complex. We identified stabilization clusters in the GTPase and helical domains responsible for structural integrity and the conformational changes associated with activation. In activation cluster I, helices α1 and α5 pack against strands β1-β3 to stabilize the nucleotide-bound states...
September 2015: Nature Structural & Molecular Biology
Rita Gemayel, Sreenivas Chavali, Ksenia Pougach, Matthieu Legendre, Bo Zhu, Steven Boeynaems, Elisa van der Zande, Kris Gevaert, Frederic Rousseau, Joost Schymkowitz, M Madan Babu, Kevin J Verstrepen
Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington's disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes...
August 20, 2015: Molecular Cell
Anna R Panchenko, M Madan Babu
No abstract text is available yet for this article.
June 2015: Current Opinion in Structural Biology
Tilman Flock, Charles N J Ravarani, Dawei Sun, A J Venkatakrishnan, Melis Kayikci, Christopher G Tate, Dmitry B Veprintsev, M Madan Babu
G protein-coupled receptors (GPCRs) allosterically activate heterotrimeric G proteins and trigger GDP release. Given that there are ∼800 human GPCRs and 16 different Gα genes, this raises the question of whether a universal allosteric mechanism governs Gα activation. Here we show that different GPCRs interact with and activate Gα proteins through a highly conserved mechanism. Comparison of Gα with the small G protein Ras reveals how the evolution of short segments that undergo disorder-to-order transitions can decouple regions important for allosteric activation from receptor binding specificity...
August 13, 2015: Nature
Marie Schrynemackers, Louis Wehenkel, M Madan Babu, Pierre Geurts
Networks are ubiquitous in biology, and computational approaches have been largely investigated for their inference. In particular, supervised machine learning methods can be used to complete a partially known network by integrating various measurements. Two main supervised frameworks have been proposed: the local approach, which trains a separate model for each network node, and the global approach, which trains a single model over pairs of nodes. Here, we systematically investigate, theoretically and empirically, the exploitation of tree-based ensemble methods in the context of these two approaches for biological network inference...
August 2015: Molecular BioSystems
Natasha S Latysheva, Tilman Flock, Robert J Weatheritt, Sreenivas Chavali, M Madan Babu
The traditional structure to function paradigm conceives of a protein's function as emerging from its structure. In recent years, it has been established that unstructured, intrinsically disordered regions (IDRs) in proteins are equally crucial elements for protein function, regulation and homeostasis. In this review, we provide a brief overview of how IDRs can perform similar functions to structured proteins, focusing especially on the formation of protein complexes and assemblies and the mediation of regulated conformational changes...
June 2015: Protein Science: a Publication of the Protein Society
Natalia Sanchez de Groot, Ricardo A Gomes, Anna Villar-Pique, M Madan Babu, Ana Varela Coelho, Salvador Ventura
Proteins adopt defined structures and are crucial to most cellular functions. Their misfolding and aggregation is associated with numerous degenerative human disorders such as type II diabetes, Huntington's or Alzheimer's diseases. Here, we aim to understand why cells promote the formation of protein foci. Comparison of two amyloid-β-peptide variants, mostly insoluble but differently recruited by the cell (inclusion body versus diffused), reveals small differences in cell fitness and proteome response. We suggest that the levels of oxidative stress act as a sensor to trigger protein recruitment into foci...
February 2015: Open Biology
Susan Fishbain, Tomonao Inobe, Eitan Israeli, Sreenivas Chavali, Houqing Yu, Grace Kago, M Madan Babu, Andreas Matouschek
The proteasome controls the concentrations of most proteins in eukaryotic cells. It recognizes its protein substrates through ubiquitin tags and initiates degradation at disordered regions within the substrate. Here we show that the proteasome has pronounced preferences for the amino acid sequence of the regions at which it initiates degradation. Specifically, proteins in which the initiation regions have biased amino acid compositions show longer half-lives in yeast than proteins with unbiased sequences in the regions...
March 2015: Nature Structural & Molecular Biology
Hiroyoshi Hattori, Rekin's Janky, Wilfried Nietfeld, Stein Aerts, M Madan Babu, Ashok R Venkitaraman
The human DNA damage response (DDR) triggers profound changes in gene expression, whose nature and regulation remain uncertain. Although certain micro-(mi)RNA species including miR34, miR-18, miR-16 and miR-143 have been implicated in the DDR, there is as yet no comprehensive description of genome-wide changes in the expression of miRNAs triggered by DNA breakage in human cells. We have used next-generation sequencing (NGS), combined with rigorous integrative computational analyses, to describe genome-wide changes in the expression of miRNAs during the human DDR...
2014: Cell Cycle
Alexey S Morgunov, M Madan Babu
No abstract text is available yet for this article.
December 2014: Nature Structural & Molecular Biology
Robin van der Lee, Benjamin Lang, Kai Kruse, Jörg Gsponer, Natalia Sánchez de Groot, Martijn A Huynen, Andreas Matouschek, Monika Fuxreiter, M Madan Babu
Precise control of protein turnover is essential for cellular homeostasis. The ubiquitin-proteasome system is well established as a major regulator of protein degradation, but an understanding of how inherent structural features influence the lifetimes of proteins is lacking. We report that yeast, mouse, and human proteins with terminal or internal intrinsically disordered segments have significantly shorter half-lives than proteins without these features. The lengths of the disordered segments that affect protein half-life are compatible with the structure of the proteasome...
September 25, 2014: Cell Reports
A J Venkatakrishnan, Tilman Flock, Daniel Estévez Prado, Matt E Oates, Julian Gough, M Madan Babu
The seven-transmembrane (7TM) helix fold of G-protein coupled receptors (GPCRs) has been adapted for a wide variety of physiologically important signaling functions. Here, we discuss the diversity in the structured and disordered regions of GPCRs based on the recently published crystal structures and sequence analysis of all human GPCRs. A comparison of the structures of rhodopsin-like receptors (class A), secretin-like receptors (class B), metabotropic receptors (class C) and frizzled receptors (class F) shows that the relative arrangement of the transmembrane helices is conserved across all four GPCR classes although individual receptors can be activated by ligand binding at varying positions within and around the transmembrane helical bundle...
August 2014: Current Opinion in Structural Biology
Robert J Weatheritt, Toby J Gibson, M Madan Babu
Although many proteins are localized after translation, asymmetric protein distribution is also achieved by translation after mRNA localization. Why are certain mRNA transported to a distal location and translated on-site? Here we undertake a systematic, genome-scale study of asymmetrically distributed protein and mRNA in mammalian cells. Our findings suggest that asymmetric protein distribution by mRNA localization enhances interaction fidelity and signaling sensitivity. Proteins synthesized at distal locations frequently contain intrinsically disordered segments...
September 2014: Nature Structural & Molecular Biology
Peter Tompa, Norman E Davey, Toby J Gibson, M Madan Babu
A molecular description of functional modules in the cell is the focus of many high-throughput studies in the postgenomic era. A large portion of biomolecular interactions in virtually all cellular processes is mediated by compact interaction modules, referred to as peptide motifs. Such motifs are typically less than ten residues in length, occur within intrinsically disordered regions, and are recognized and/or posttranslationally modified by structured domains of the interacting partner. In this review, we suggest that there might be over a million instances of peptide motifs in the human proteome...
July 17, 2014: Molecular Cell
Tilman Flock, Robert J Weatheritt, Natasha S Latysheva, M Madan Babu
Intrinsically disordered regions (IDRs) are fundamental units of protein function and regulation. Despite their inability to form a unique stable tertiary structure in isolation, many IDRs adopt a defined conformation upon binding and achieve their function through their interactions with other biomolecules. However, this requirement for IDR functionality seems to be at odds with the high entropic cost they must incur upon binding an interaction partner. How is this seeming paradox resolved? While increasing the enthalpy of binding is one approach to compensate for this entropic cost, growing evidence suggests that inherent features of IDRs, for instance repeating linear motifs, minimise the entropic cost of binding...
June 2014: Current Opinion in Structural Biology
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