scholarly journals Biological impact of mutually exclusive exon switching

2021 ◽  
Vol 17 (3) ◽  
pp. e1008708
Author(s):  
Su Datt Lam ◽  
M. Madan Babu ◽  
Jonathan Lees ◽  
Christine A. Orengo
Keyword(s):  
Alternative Splicing ◽  
Structural Properties ◽  
Protein Function ◽  
Large Scale ◽  
Large Scale Structure ◽  
Protein Fold ◽  
Protein Surface ◽  
Biological Impact ◽  
Functional Sites ◽  
Exclusive Exon

Alternative splicing can expand the diversity of proteomes. Homologous mutually exclusive exons (MXEs) originate from the same ancestral exon and result in polypeptides with similar structural properties but altered sequence. Why would some genes switch homologous exons and what are their biological impact? Here, we analyse the extent of sequence, structural and functional variability in MXEs and report the first large scale, structure-based analysis of the biological impact of MXE events from different genomes. MXE-specific residues tend to map to single domains, are highly enriched in surface exposed residues and cluster at or near protein functional sites. Thus, MXE events are likely to maintain the protein fold, but alter specificity and selectivity of protein function. This comprehensive resource of MXE events and their annotations is available at: http://gene3d.biochem.ucl.ac.uk/mxemod/. These findings highlight how small, but significant changes at critical positions on a protein surface are exploited in evolution to alter function.

scholarly journals iProteinDB: an integrative database of Drosophila post-translational modifications

2018 ◽  
Author(s):  
Yanhui Hu ◽  
Richelle Sopko ◽  
Verena Chung ◽  
Romain A. Studer ◽  
Sean D. Landry ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Function ◽  
Large Scale ◽  
Model Organisms ◽  
General Strategy ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Functional Sites ◽  
Evolutionarily Conserved ◽  
And Function

AbstractPost-translational modification (PTM) serves as a regulatory mechanism for protein function, influencing stability, protein interactions, activity and localization, and is critical in many signaling pathways. The best characterized PTM is phosphorylation, whereby a phosphate is added to an acceptor residue, commonly serine, threonine and tyrosine. As proteins are often phosphorylated at multiple sites, identifying those sites that are important for function is a challenging problem. Considering that many phosphorylation sites may be non-functional, prioritizing evolutionarily conserved phosphosites provides a general strategy to identify the putative functional sites with regards to regulation and function. To facilitate the identification of conserved phosphosites, we generated a large-scale phosphoproteomics dataset from Drosophila embryos collected from six closely-related species. We built iProteinDB (https://www.flyrnai.org/tools/iproteindb/), a resource integrating these data with other high-throughput PTM datasets, including vertebrates, and manually curated information for Drosophila. At iProteinDB, scientists can view the PTM landscape for any Drosophila protein and identify predicted functional phosphosites based on a comparative analysis of data from closely-related Drosophila species. Further, iProteinDB enables comparison of PTM data from Drosophila to that of orthologous proteins from other model organisms, including human, mouse, rat, Xenopus laevis, Danio rerio, and Caenorhabditis elegans.

scholarly journals Large Scale Structure Sampling for Protein Fold Prediction using the Generalized Simulated Annealing

2013 ◽  
Vol 104 (2) ◽  
pp. 228a-229a ◽  
Author(s):  
Marcelo C.R. Melo ◽  
Rafael C. Bernardi ◽  
Pedro G. Pascutti
Keyword(s):  
Simulated Annealing ◽  
Large Scale ◽  
Large Scale Structure ◽  
Scale Structure ◽  
Protein Fold ◽  
Fold Prediction

scholarly journals Robust Classification of Protein Variation Using Structural Modeling and Large-Scale Data Integration

2015 ◽  
Author(s):  
Evan H. Baugh ◽  
Riley Simmons-Edler ◽  
Christian L. Mueller ◽  
Rebecca F. Alford ◽  
Natalia Volfovsky ◽  
...  
Keyword(s):  
Protein Function ◽  
Large Scale ◽  
De Novo ◽  
Structural Diversity ◽  
Structural Modeling ◽  
Autism Spectrum ◽  
Human Diseases ◽  
Functional Sites ◽  
Protein Variation ◽  
Protein Variants

Existing methods for interpreting protein variation focus on annotating mutation pathogenicity rather than detailed interpretation of variant deleteriousness and frequently use only sequence-based or structure-based information. We present VIPUR, a computational framework that seamlessly integrates sequence analysis and structural modeling (using the Rosetta protein modeling suite) to identify and interpret deleterious protein variants. To train VIPUR, we collected 9,477 protein variants with known effects on protein function from multiple organisms and curated structural models for each variant from crystal structures and homology models. VIPUR can be applied to mutations in any organism's proteome with improved generalized accuracy (AUROC .83) and interpretability (AUPR .87) compared to other methods. We demonstrate that VIPUR's predictions of deleteriousness match the biological phenotypes in ClinVar and provide a clear ranking of prediction confidence. We use VIPUR to interpret known mutations associated with inflammation and diabetes, demonstrating the structural diversity of disrupted functional sites and improved interpretation of mutations associated with human diseases. Lastly we demonstrate VIPUR's ability to highlight candidate genes associated with human diseases by applying VIPUR to de novo variants associated with autism spectrum disorders.

Zeitstrukturen im Jazz

2014 ◽  
Vol 59 (1) ◽  
pp. 79-92
Author(s):  
Alexander Becker
Keyword(s):  
Large Scale ◽  
Large Scale Structure ◽  
Time Frame ◽  
Scale Structure ◽  
Classical Form ◽  
Jazz Music ◽  
The Moment

Wie erlebt der Hörer Jazz? Bei dieser Frage geht es unter anderem um die Art und Weise, wie Jazz die Zeit des Hörens gestaltet. Ein an klassischer Musik geschultes Ohr erwartet von musikalischer Zeitgestaltung, den zeitlichen Rahmen, der durch Anfang und Ende gesetzt ist, von innen heraus zu strukturieren und neu zu konstituieren. Doch das ist keine Erwartung, die dem Jazz gerecht wird. Im Jazz wird der Moment nicht im Hinblick auf ein Ziel gestaltet, das von einer übergeordneten Struktur bereitgestellt wird, sondern so, dass er den Bewegungsimpuls zum nächsten Moment weiterträgt. Wie wirkt sich dieses Prinzip der Zeitgestaltung auf die musikalische Form im Großen aus? Der Aufsatz untersucht diese Frage anhand von Beispielen, an denen sich der Weg der Transformation von einer klassischen zu einer dem Jazz angemessenen Form gut nachverfolgen lässt.<br><br>How do listeners experience Jazz? This is a question also about how Jazz music organizes the listening time. A classically educated listener expects a piece of music to structure, unify and thereby re-constitute the externally given time frame. Such an expectation is foreign to Jazz music which doesn’t relate the moment to a goal provided by a large scale structure. Rather, one moment is carried on to the next, preserving the stimulus potentially ad infinitum. How does such an organization of time affect the large scale form? The paper tries to answer this question by analyzing two examples which permit to trace the transformation of a classical form into a form germane to Jazz music.

scholarly journals PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Dawei Chen ◽  
Zhenguo Zhao ◽  
Lu Chen ◽  
Qinghua Li ◽  
Jixue Zou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Alternative Splicing ◽  
Protein Function ◽  
Vital Role ◽  
Normal Tissues ◽  
Mechanistic Analysis ◽  
Highly Correlated ◽  
Splicing Patterns

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

scholarly journals Mapping large-scale-structure evolution over cosmic times

2021 ◽  
Author(s):  
Marta B. Silva ◽  
Ely D. Kovetz ◽  
Garrett K. Keating ◽  
Azadeh Moradinezhad Dizgah ◽  
Matthieu Bethermin ◽  
...  
Keyword(s):  
Galaxy Formation ◽  
Large Scale ◽  
High Redshift ◽  
Formation Rate ◽  
Far Infrared ◽  
Large Scale Structure ◽  
Scale Structure ◽  
Structure Evolution ◽  
Intensity Mapping ◽  
Wide Range

AbstractThis paper outlines the science case for line-intensity mapping with a space-borne instrument targeting the sub-millimeter (microwaves) to the far-infrared (FIR) wavelength range. Our goal is to observe and characterize the large-scale structure in the Universe from present times to the high redshift Epoch of Reionization. This is essential to constrain the cosmology of our Universe and form a better understanding of various mechanisms that drive galaxy formation and evolution. The proposed frequency range would make it possible to probe important metal cooling lines such as [CII] up to very high redshift as well as a large number of rotational lines of the CO molecule. These can be used to trace molecular gas and dust evolution and constrain the buildup in both the cosmic star formation rate density and the cosmic infrared background (CIB). Moreover, surveys at the highest frequencies will detect FIR lines which are used as diagnostics of galaxies and AGN. Tomography of these lines over a wide redshift range will enable invaluable measurements of the cosmic expansion history at epochs inaccessible to other methods, competitive constraints on the parameters of the standard model of cosmology, and numerous tests of dark matter, dark energy, modified gravity and inflation. To reach these goals, large-scale structure must be mapped over a wide range in frequency to trace its time evolution and the surveyed area needs to be very large to beat cosmic variance. Only a space-borne mission can properly meet these requirements.

scholarly journals Higher order Hamiltonian Monte Carlo sampling for cosmological large-scale structure analysis

2021 ◽  
Vol 502 (3) ◽  
pp. 3976-3992
Author(s):  
Mónica Hernández-Sánchez ◽  
Francisco-Shu Kitaura ◽  
Metin Ata ◽  
Claudio Dalla Vecchia
Keyword(s):  
Fourth Order ◽  
Large Scale ◽  
Equations Of Motion ◽  
Large Scale Structure ◽  
Real Space ◽  
Higher Order ◽  
Second Order ◽  
Scale Structure ◽  
Integration Schemes ◽  
Reconstruction Methods

ABSTRACT We investigate higher order symplectic integration strategies within Bayesian cosmic density field reconstruction methods. In particular, we study the fourth-order discretization of Hamiltonian equations of motion (EoM). This is achieved by recursively applying the basic second-order leap-frog scheme (considering the single evaluation of the EoM) in a combination of even numbers of forward time integration steps with a single intermediate backward step. This largely reduces the number of evaluations and random gradient computations, as required in the usual second-order case for high-dimensional cases. We restrict this study to the lognormal-Poisson model, applied to a full volume halo catalogue in real space on a cubical mesh of 1250 h−1 Mpc side and 2563 cells. Hence, we neglect selection effects, redshift space distortions, and displacements. We note that those observational and cosmic evolution effects can be accounted for in subsequent Gibbs-sampling steps within the COSMIC BIRTH algorithm. We find that going from the usual second to fourth order in the leap-frog scheme shortens the burn-in phase by a factor of at least ∼30. This implies that 75–90 independent samples are obtained while the fastest second-order method converges. After convergence, the correlation lengths indicate an improvement factor of about 3.0 fewer gradient computations for meshes of 2563 cells. In the considered cosmological scenario, the traditional leap-frog scheme turns out to outperform higher order integration schemes only when considering lower dimensional problems, e.g. meshes with 643 cells. This gain in computational efficiency can help to go towards a full Bayesian analysis of the cosmological large-scale structure for upcoming galaxy surveys.

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