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M Madan Babu

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https://www.readbyqxmd.com/read/29590031/capturing-dynamic-protein-interactions
#1
COMMENT
Xiao-Han Li, Pavithra L Chavali, M Madan Babu
No abstract text is available yet for this article.
March 9, 2018: Science
https://www.readbyqxmd.com/read/29434345/cotranslational-protein-assembly-imposes-evolutionary-constraints-on-homomeric-proteins
#2
Eviatar Natan, Tamaki Endoh, Liora Haim-Vilmovsky, Tilman Flock, Guilhem Chalancon, Jonathan T S Hopper, Bálint Kintses, Peter Horvath, Lejla Daruka, Gergely Fekete, Csaba Pál, Balázs Papp, Erika Oszi, Zoltán Magyar, Joseph A Marsh, Adrian H Elcock, M Madan Babu, Carol V Robinson, Naoki Sugimoto, Sarah A Teichmann
Cotranslational protein folding can facilitate rapid formation of functional structures. However, it can also cause premature assembly of protein complexes, if two interacting nascent chains are in close proximity. By analyzing known protein structures, we show that homomeric protein contacts are enriched toward the C termini of polypeptide chains across diverse proteomes. We hypothesize that this is the result of evolutionary constraints for folding to occur before assembly. Using high-throughput imaging of protein homomers in Escherichia coli and engineered protein constructs with N- and C-terminal oligomerization domains, we show that, indeed, proteins with C-terminal homomeric interface residues consistently assemble more efficiently than those with N-terminal interface residues...
March 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29392932/function-and-regulation-of-phase-separated-biological-condensates
#3
Xiao-Han Li, Pavithra L Chavali, Rita Pancsa, Sreenivas Chavali, M Madan Babu
Achieving functional specificity while minimizing cost to fitness is a key constraint during evolution. Formation of biological condensates by liquid-liquid phase separation (LLPS) appears to serve as an important regulatory mechanism to generate moderate specificity in molecular recognition while maintaining a reasonable cost for fitness in terms of design complexity. Formation of biological condensates serves as a unique mechanism of molecular recognition achieving some level of specificity without a huge cost to fitness...
February 12, 2018: Biochemistry
https://www.readbyqxmd.com/read/29362230/contrasting-function-of-structured-n-terminal-and-unstructured-c-terminal-segments-of-mycobacterium-tuberculosis-ppe37-protein
#4
Javeed Ahmad, Aisha Farhana, Rita Pancsa, Simran Kaur Arora, Alagiri Srinivasan, Anil Kumar Tyagi, Madan Mohan Babu, Nasreen Zafar Ehtesham, Seyed Ehtesham Hasnain
Pathogens frequently employ eukaryotic linear motif (ELM)-rich intrinsically disordered proteins (IDPs) to perturb and hijack host cell networks for a productive infection. Mycobacterium tuberculosis has a relatively high percentage of IDPs in its proteome, the significance of which is not known. The Mycobacterium-specific PE-PPE protein family has several members with unusually high levels of structural disorder and disorder-promoting Ala/Gly residues. PPE37 protein, a member of this family, carries an N-terminal PPE domain capable of iron binding, two transmembrane domains, and a disordered C-terminal segment harboring ELMs and a eukaryotic nuclear localization signal (NLS)...
January 23, 2018: MBio
https://www.readbyqxmd.com/read/29335563/visualization-and-analysis-of-non-covalent-contacts-using-the-protein-contacts-atlas
#5
Melis Kayikci, A J Venkatakrishnan, James Scott-Brown, Charles N J Ravarani, Tilman Flock, M Madan Babu
Visualizations of biomolecular structures empower us to gain insights into biological functions, generate testable hypotheses, and communicate biological concepts. Typical visualizations (such as ball and stick) primarily depict covalent bonds. In contrast, non-covalent contacts between atoms, which govern normal physiology, pathogenesis, and drug action, are seldom visualized. We present the Protein Contacts Atlas, an interactive resource of non-covalent contacts from over 100,000 PDB crystal structures. We developed multiple representations for visualization and analysis of non-covalent contacts at different scales of organization: atoms, residues, secondary structure, subunits, and entire complexes...
February 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29249361/pharmacogenomics-of-gpcr-drug-targets
#6
Alexander S Hauser, Sreenivas Chavali, Ikuo Masuho, Leonie J Jahn, Kirill A Martemyanov, David E Gloriam, M Madan Babu
Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health. Although 108 G-protein-coupled receptors (GPCRs) are the targets of 475 (∼34%) Food and Drug Administration (FDA)-approved drugs and account for a global sales volume of over 180 billion US dollars annually, the prevalence of genetic variation among GPCRs targeted by drugs is unknown. By analyzing data from 68,496 individuals, we find that GPCRs targeted by drugs show genetic variation within functional regions such as drug- and effector-binding sites in the human population...
January 11, 2018: Cell
https://www.readbyqxmd.com/read/29045845/revealing-the-determinants-of-widespread-alternative-splicing-perturbation-in-cancer
#7
Yongsheng Li, Nidhi Sahni, Rita Pancsa, Daniel J McGrail, Juan Xu, Xu Hua, Jasmin Coulombe-Huntington, Michael Ryan, Boranai Tychhon, Dhanistha Sudhakar, Limei Hu, Michael Tyers, Xiaoqian Jiang, Shiaw-Yih Lin, M Madan Babu, Song Yi
It is increasingly appreciated that alternative splicing plays a key role in generating functional specificity and diversity in cancer. However, the mechanisms by which cancer mutations perturb splicing remain unknown. Here, we developed a network-based strategy, DrAS-Net, to investigate more than 2.5 million variants across cancer types and link somatic mutations with cancer-specific splicing events. We identified more than 40,000 driver variant candidates and their 80,000 putative splicing targets deregulated in 33 cancer types and inferred their functional impact...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/28805808/constraints-and-consequences-of-the-emergence-of-amino-acid-repeats-in-eukaryotic-proteins
#8
Sreenivas Chavali, Pavithra L Chavali, Guilhem Chalancon, Natalia Sanchez de Groot, Rita Gemayel, Natasha S Latysheva, Elizabeth Ing-Simmons, Kevin J Verstrepen, Santhanam Balaji, M Madan Babu
Proteins with amino acid homorepeats have the potential to be detrimental to cells and are often associated with human diseases. Why, then, are homorepeats prevalent in eukaryotic proteomes? In yeast, homorepeats are enriched in proteins that are essential and pleiotropic and that buffer environmental insults. The presence of homorepeats increases the functional versatility of proteins by mediating protein interactions and facilitating spatial organization in a repeat-dependent manner. During evolution, homorepeats are preferentially retained in proteins with stringent proteostasis, which might minimize repeat-associated detrimental effects such as unregulated phase separation and protein aggregation...
September 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28489817/selectivity-determinants-of-gpcr-g-protein-binding
#9
Tilman Flock, Alexander S Hauser, Nadia Lund, David E Gloriam, Santhanam Balaji, M Madan Babu
The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts...
May 18, 2017: Nature
https://www.readbyqxmd.com/read/28487210/intrinsically-disordered-proteins-adaptively-reorganize-cellular-matter-during-stress
#10
Sreenivas Chavali, Alexander Gunnarsson, M Madan Babu
Intrinsically disordered proteins (IDPs) can protect cells from diverse stresses by forming higher order assemblies such as reversible aggregates or granules. Recently, Boothby et al. show that IDPs protect tardigrades against desiccation by forming a glass-like amorphous matrix, highlighting that material properties of disordered proteins can confer adaptation during stress.
June 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28328918/simultaneous-quantification-of-protein-order-and-disorder
#11
Pietro Sormanni, Damiano Piovesan, Gabriella T Heller, Massimiliano Bonomi, Predrag Kukic, Carlo Camilloni, Monika Fuxreiter, Zsuzsanna Dosztanyi, Rohit V Pappu, M Madan Babu, Sonia Longhi, Peter Tompa, A Keith Dunker, Vladimir N Uversky, Silvio C E Tosatto, Michele Vendruscolo
No abstract text is available yet for this article.
March 22, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/27911701/the-contribution-of-intrinsically-disordered-regions-to-protein-function-cellular-complexity-and-human-disease
#12
REVIEW
M Madan Babu
In the 1960s, Christian Anfinsen postulated that the unique three-dimensional structure of a protein is determined by its amino acid sequence. This work laid the foundation for the sequence-structure-function paradigm, which states that the sequence of a protein determines its structure, and structure determines function. However, a class of polypeptide segments called intrinsically disordered regions does not conform to this postulate. In this review, I will first describe established and emerging ideas about how disordered regions contribute to protein function...
October 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27540857/molecular-principles-of-gene-fusion-mediated-rewiring-of-protein-interaction-networks-in-cancer
#13
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
https://www.readbyqxmd.com/read/27525504/diverse-activation-pathways-in-class-a-gpcrs-converge-near-the-g-protein-coupling-region
#14
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
https://www.readbyqxmd.com/read/27226608/conserved-sequence-preferences-contribute-to-substrate-recognition-by-the-proteasome
#15
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
https://www.readbyqxmd.com/read/27105842/discovering-and-understanding-oncogenic-gene-fusions-through-data-intensive-computational-approaches
#16
REVIEW
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
https://www.readbyqxmd.com/read/26832815/affinity-and-competition-for-tbp-are-molecular-determinants-of-gene-expression-noise
#17
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
https://www.readbyqxmd.com/read/26258638/probing-g%C3%AE-i1-protein-activation-at-single-amino-acid-resolution
#18
Dawei Sun, Tilman Flock, Xavier Deupi, Shoji Maeda, Milos Matkovic, Sandro Mendieta, Daniel Mayer, Roger 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
https://www.readbyqxmd.com/read/26257283/variable-glutamine-rich-repeats-modulate-transcription-factor-activity
#19
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
https://www.readbyqxmd.com/read/26199202/editorial-overview-linking-protein-sequence-and-structural-changes-to-function-in-the-era-of-next-generation-sequencing
#20
EDITORIAL
Anna R Panchenko, M Madan Babu
No abstract text is available yet for this article.
June 2015: Current Opinion in Structural Biology
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