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Jorg Gsponer

Nawar Malhis, Matthew Jacobson, Jörg Gsponer
Molecular recognition features, MoRFs, are short segments within longer disordered protein regions that bind to globular protein domains in a process known as disorder-to-order transition. MoRFs have been found to play a significant role in signaling and regulatory processes in cells. High-confidence computational identification of MoRFs remains an important challenge. In this work, we introduce MoRFchibi SYSTEM that contains three MoRF predictors: MoRFCHiBi, a basic predictor best suited as a component in other applications, MoRFCHiBi_ Light, ideal for high-throughput predictions and MoRFCHiBi_ Web, slower than the other two but best for high accuracy predictions...
July 8, 2016: Nucleic Acids Research
Ju Hun Yeon, Florian Heinkel, Minhui Sung, Dokyun Na, Jörg Gsponer
Protein interactions in cis that can activate or autoinhibit protein function play an important role in the fine-tuning of regulatory and signaling processes in the cell, but thus far cis-regulatory elements (CREs) in proteins have not been systematically identified and studied. Here, we introduce a computational tool that identifies intrinsically disordered protein segments that contribute to protein function regulation via interactions in cis. We apply this tool to estimate the prevalence of CREs in the human proteome and reveal that cis regulation is enriched in several signaling pathways, including the MAP kinase pathway, for which we provide a detailed map of its "cis regulome...
February 24, 2016: Cell Systems
Alexander Cumberworth, Jennifer M Bui, Jörg Gsponer
Implicit solvent models for biomolecular simulations have been developed to use in place of more expensive explicit models; however, these models make many assumptions and approximations that are likely to affect accuracy. Here, the changes in free energies of solvation upon folding ΔΔGsolv of several fast folding proteins are calculated from previously run μs-ms simulations with a number of implicit solvent models and compared to the values needed to be consistent with the explicit solvent model used in the simulations...
March 15, 2016: Journal of Computational Chemistry
Florian Heinkel, Jörg Gsponer
The mapping of folding landscapes remains an important challenge in protein chemistry. Pulsed oxidative labeling of exposed residues and their detection via mass spectrometry provide new means of taking time-resolved "snapshots" of the structural changes that occur during protein folding. However, such experiments have been so far only interpreted qualitatively. Here, we report the detailed structural interpretation of mass spectrometry data from fast photochemical oxidation of proteins (FPOP) experiments at atomic resolution in a biased molecular dynamics approach...
January 29, 2016: Journal of Molecular Biology
Nawar Malhis, Jörg Gsponer
MOTIVATION: Intrinsically disordered regions of proteins play an essential role in the regulation of various biological processes. Key to their regulatory function is the binding of molecular recognition features (MoRFs) to globular protein domains in a process known as a disorder-to-order transition. Predicting the location of MoRFs in protein sequences with high accuracy remains an important computational challenge. METHOD: In this study, we introduce MoRFCHiBi, a new computational approach for fast and accurate prediction of MoRFs in protein sequences...
June 1, 2015: Bioinformatics
Dokyun Na, Hyungbin Son, Jörg Gsponer
BACKGROUND: Communalities between large sets of genes obtained from high-throughput experiments are often identified by searching for enrichments of genes with the same Gene Ontology (GO) annotations. The GO analysis tools used for these enrichment analyses assume that GO terms are independent and the semantic distances between all parent-child terms are identical, which is not true in a biological sense. In addition these tools output lists of often redundant or too specific GO terms, which are difficult to interpret in the context of the biological question investigated by the user...
2014: BMC Genomics
Razvan F Albu, Gerard T Chan, Mang Zhu, Eric T C Wong, Farnaz Taghizadeh, Xiaoke Hu, Arya E Mehran, James D Johnson, Jörg Gsponer, Thibault Mayor
UNLABELLED: Because misfolded and damaged proteins can form potentially harmful aggregates, all living organisms have evolved a wide variety of quality control mechanisms. However, the timely clearance of aggregation-prone species may not always be achieved, potentially leading to the accumulation of low solubility proteins. At the same time, promiscuity, which can be a driving force for aggregation, is also important to the functionality of certain proteins which have a large number of interaction partners...
April 6, 2015: Journal of Proteomics
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
Guillaume Lamour, Julius B Kirkegaard, Hongbin Li, Tuomas Pj Knowles, Jörg Gsponer
BACKGROUND: A growing spectrum of applications for natural and synthetic polymers, whether in industry or for biomedical research, demands for fast and universally applicable tools to determine the mechanical properties of very diverse polymers. To date, determining these properties is the privilege of a limited circle of biophysicists and engineers with appropriate technical skills. FINDINGS: Easyworm is a user-friendly software suite coded in MATLAB that simplifies the image analysis of individual polymeric chains and the extraction of the mechanical properties of these chains...
2014: Source Code for Biology and Medicine
Jennifer M Bui, Jörg Gsponer
Functions of many proteins are affected by posttranslational modifications of intrinsically disordered (ID) regions, yet little is known about the underlying molecular mechanisms. By combining molecular dynamics simulations and protein docking, we demonstrate that the addition of phosphates to an ID segment adjacent to the PNT domain of Ets1 directs conformational sampling toward substates that are most compatible with high-affinity binding of the TAZ1 domain of its coactivator CBP. The phosphate charges disrupt salt bridges and thereby open a hydrophobic cleft and expose hydrophobic residues at the ID N terminus...
August 5, 2014: Structure
Guillaume Lamour, Calvin K Yip, Hongbin Li, Jörg Gsponer
Self-templated protein aggregation and intracerebral deposition of aggregates, sometimes in the form of amyloid fibrils, is a hallmark of mammalian prion diseases. What distinguishes amyloid fibrils formed by prions from those formed by other proteins is not clear. On the basis of previous studies on yeast prions that correlated high intrinsic fragmentation rates of fibrils with prion propagation efficiency, it has been hypothesized that the nanomechanical properties of prion amyloid such as strength and elastic modulus may be the distinguishing feature...
April 22, 2014: ACS Nano
Dokyun Na, Mushfiqur Rouf, Cahir J O'Kane, David C Rubinsztein, Jörg Gsponer
BACKGROUND: Neurodegenerative diseases (NDs) are characterized by the progressive loss of neurons in the human brain. Although the majority of NDs are sporadic, evidence is accumulating that they have a strong genetic component. Therefore, significant efforts have been made in recent years to not only identify disease-causing genes but also genes that modify the severity of NDs, so-called genetic modifiers. To date there exists no compendium that lists and cross-links genetic modifiers of different NDs...
2013: BMC Medical Genomics
Eric T C Wong, Dokyun Na, Jörg Gsponer
There is a growing recognition for the importance of proteins with large intrinsically disordered (ID) segments in cell signaling and regulation. ID segments in these proteins often harbor regions that mediate molecular recognition. Coupled folding and binding of the recognition regions has been proposed to confer high specificity to interactions involving ID segments. However, researchers recently questioned the origin of the interaction specificity of ID proteins because of the overrepresentation of hydrophobic residues in their interaction interfaces...
2013: PLoS Computational Biology
Alexander Cumberworth, Guillaume Lamour, M Madan Babu, Jörg Gsponer
Because of their pervasiveness in eukaryotic genomes and their unique properties, understanding the role that ID (intrinsically disordered) regions in proteins play in the interactome is essential for gaining a better understanding of the network. Especially critical in determining this role is their ability to bind more than one partner using the same region. Studies have revealed that proteins containing ID regions tend to take a central role in protein interaction networks; specifically, they act as hubs, interacting with multiple different partners across time and space, allowing for the co-ordination of many cellular activities...
September 15, 2013: Biochemical Journal
Alex H M Ng, Nancy N Fang, Sophie A Comyn, Jörg Gsponer, Thibault Mayor
Damaged and misfolded proteins that are no longer functional in the cell need to be eliminated. Failure to do so might lead to their accumulation and aggregation, a hallmark of many neurodegenerative diseases. Protein quality control pathways play a major role in the degradation of these proteins, which is mediated mainly by the ubiquitin proteasome system. Despite significant focus on identifying ubiquitin ligases involved in these pathways, along with their substrates, a systems-level understanding of these pathways has been lacking...
September 2013: Molecular & Cellular Proteomics: MCP
Travis Trudeau, Roy Nassar, Alexander Cumberworth, Eric T C Wong, Geoffrey Woollard, Jörg Gsponer
Autoinhibition plays a significant role in the regulation of many proteins. By analyzing autoinhibited proteins, we demonstrate that these proteins are enriched in intrinsic disorder because of the properties of their inhibitory modules (IMs). A comparison of autoinhibited proteins with structured and intrinsically disordered IMs revealed that in the latter group (1) multiple phosphorylation sites are highly abundant; (2) splice variants occur in greater number than in their structured cousins; and (3) activation is often associated with changes in secondary structure in the IM...
March 5, 2013: Structure
Yongnan Devin Li, Guillaume Lamour, Jörg Gsponer, Peng Zheng, Hongbin Li
Mechanical responses of elastic proteins are crucial for their biological function and nanotechnological use. Loading direction has been identified as one key determinant for the mechanical responses of proteins. However, it is not clear how a change in pulling direction changes the mechanical unfolding mechanism of the protein. Here, we combine protein engineering, single-molecule force spectroscopy, and steered molecular dynamics simulations to systematically investigate the mechanical response of a small globular protein GB1...
December 5, 2012: Biophysical Journal
Jörg Gsponer, M Madan Babu
Growing evidence suggests that aggregation-prone proteins are both harmful and functional for a cell. How do cellular systems balance the detrimental and beneficial effect of protein aggregation? We reveal that aggregation-prone proteins are subject to differential transcriptional, translational, and degradation control compared to nonaggregation-prone proteins, which leads to their decreased synthesis, low abundance, and high turnover. Genetic modulators that enhance the aggregation phenotype are enriched in genes that influence expression homeostasis...
November 29, 2012: Cell Reports
Natalia Sanchez de Groot, Marc Torrent, Anna Villar-Piqué, Benjamin Lang, Salvador Ventura, Jörg Gsponer, M Madan Babu
Protein aggregation is being found to be associated with an increasing number of human diseases. Aggregation can lead to a loss of function (lack of active protein) or to a toxic gain of function (cytotoxicity associated with protein aggregates). Although potentially harmful, protein sequences predisposed to aggregation seem to be ubiquitous in all kingdoms of life, which suggests an evolutionary advantage to having such segments in polypeptide sequences. In fact, aggregation-prone segments are essential for protein folding and for mediating certain protein-protein interactions...
October 2012: Biochemical Society Transactions
Katja Scheffler, Markus Krohn, Tina Dunkelmann, Jan Stenzel, Bruno Miroux, Saleh Ibrahim, Oliver von Bohlen Und Halbach, Hans-Jochen Heinze, Lary C Walker, Jörg A Gsponer, Jens Pahnke
Several lines of evidence link mutations and deletions in mitochondrial DNA (mtDNA) and its maternal inheritance to neurodegenerative diseases in the elderly. Age-related mutations of mtDNA modulate the tricarboxylic cycle enzyme activity, mitochondrial oxidative phosphorylation capacity and oxidative stress response. To investigate the functional relevance of specific mtDNA polymorphisms of inbred mouse strains in the proteostasis regulation of the brain, we established novel mitochondrial congenic mouse lines of Alzheimer's disease (AD)...
August 2012: Acta Neuropathologica
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