The impact of very short alternative splicing on protein structures and functions in the human genome

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1–3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1–3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4−) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

Download Full-text

Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets

Cancers ◽

10.3390/cancers13040909 ◽

2021 ◽

Vol 13 (4) ◽

pp. 909

Author(s):

Krzysztof Kotowski ◽

Jakub Rosik ◽

Filip Machaj ◽

Stanisław Supplitt ◽

Daniel Wiczew ◽

...

Keyword(s):

Current Knowledge ◽

Treatment Options ◽

Protein Structures ◽

New Drugs ◽

Proliferating Cells ◽

Cancer Tissues ◽

The Impact ◽

Rate Limiting ◽

Synthesis And Degradation

Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options.

Download Full-text

Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies

Translational Neurodegeneration ◽

10.1186/s40035-021-00240-7 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Dunhui Li ◽

Craig Stewart McIntosh ◽

Frank Louis Mastaglia ◽

Steve Donald Wilton ◽

May Thandar Aung-Htut

Keyword(s):

Alternative Splicing ◽

Neurodegenerative Diseases ◽

Messenger Rna ◽

Muscular Atrophy ◽

Single Gene ◽

Synaptic Function ◽

Coding Regions ◽

Splicing Defects ◽

The Impact ◽

Splicing Patterns

AbstractPrecursor messenger RNA (pre-mRNA) splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions (introns) and ligates coding regions (exons) into a continuous message (mature mRNA). This process is highly regulated and can be highly flexible through a process known as alternative splicing, which allows for several transcripts to arise from a single gene, thereby greatly increasing genetic plasticity and the diversity of proteome. Alternative splicing is particularly prevalent in neuronal cells, where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis, migration and synaptic function. The continuous changes in splicing patterns and a high demand on many cis- and trans-splicing factors contribute to the susceptibility of neuronal tissues to splicing defects. The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function. Several of the most common neurodegenerative diseases involve some form of splicing defect(s), such as Alzheimer’s disease, Parkinson’s disease and spinal muscular atrophy. Our growing understanding of RNA splicing has led to the explosion of research in the field of splice-switching antisense oligonucleotide therapeutics. Here we review our current understanding of the effects alternative splicing has on neuronal differentiation, neuronal migration, synaptic maturation and regulation, as well as the impact on neurodegenerative diseases. We will also review the current landscape of splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.

Download Full-text

The Impact of the Human Genome Project on Complex Disease

Genes ◽

10.3390/genes5030518 ◽

2014 ◽

Vol 5 (3) ◽

pp. 518-535 ◽

Cited By ~ 11

Author(s):

Jessica Bailey ◽

Margaret Pericak-Vance ◽

Jonathan Haines

Keyword(s):

Human Genome ◽

Human Genome Project ◽

Complex Disease ◽

Genome Project ◽

The Human Genome Project ◽

The Impact

Download Full-text

Publics, Scientists and the State: Mapping the Global Human Genome Editing Controversy

The China Quarterly ◽

10.1017/s0305741021000229 ◽

2021 ◽

pp. 1-28

Author(s):

Ya-Wen Lei

Keyword(s):

Public Sphere ◽

Human Genome ◽

Genome Editing ◽

Scientific Research ◽

Theoretical Framework ◽

The State ◽

Scientific Controversies ◽

Chinese State ◽

National Expert ◽

The Impact

Abstract Literature on scientific controversies has inadequately attended to the impact of globalization and, more specifically, the emergence of China as a leader in scientific research. To bridge this gap in the literature, this article develops a theoretical framework to analyse global scientific controversies surrounding research in China. The framework highlights the existence of four overlapping discursive arenas: China's national public sphere and national expert sphere, the transnational public sphere and the transnational expert sphere. It then examines the struggles over inclusion/exclusion and publicity within these spheres as well as the within- and across-sphere effects of such struggles. Empirically, the article analyses the human genome editing controversy surrounding research conducted by scientists in China between 2015 and 2019. It shows how elite scientists negotiated expert–public relationships within and across the national and transnational expert spheres, how unexpected disruption at the nexus of the four spheres disrupted expert–public relationships as envisioned by elite experts, and how the Chinese state intervened to redraw the boundary between openness and secrecy at both national and transnational levels.

Download Full-text

Estrogen-related Receptor β (ERRβ) – Renaissance Receptor or Receptor Renaissance?

Nuclear Receptor Signaling ◽

10.1621/nrs.14002 ◽

2016 ◽

Vol 14 (1) ◽

pp. nrs.14002 ◽

Cited By ~ 16

Author(s):

Shailaja D. Divekar ◽

Deanna M. Tiek ◽

Aileen Fernandez ◽

Rebecca B. Riggins

Keyword(s):

Alternative Splicing ◽

Nuclear Receptor ◽

Family Members ◽

Structure And Function ◽

The Other ◽

Orphan Nuclear Receptor ◽

Nuclear Receptor Superfamily ◽

And Function ◽

The Impact ◽

Estrogen Related Receptor

Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERRα (ESRRA) and ERRγ (ESRRG) at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERRβ (ESRRB), however, has until recently been somewhat slower than that of its family members. ERRβ has also been largely ignored in summaries and perspectives of the ONR literature. Here, we provide an overview of established and emerging knowledge of ERRβ in mouse, man, and other species, highlighting unique aspects of ERRβ biology that set it apart from the other two estrogen-related receptors, with a focus on the impact of alternative splicing on the structure and function of this receptor.

Download Full-text

Factors affecting the amplitude of the τ angle in proteins: a revisitation

Acta Crystallographica Section D Structural Biology ◽

10.1107/s2059798317007793 ◽

2017 ◽

Vol 73 (7) ◽

pp. 618-625 ◽

Cited By ~ 10

Author(s):

Nicole Balasco ◽

Luciana Esposito ◽

Luigi Vitagliano

Keyword(s):

Protein Structures ◽

Factors Affecting ◽

X Ray ◽

Backbone Conformation ◽

Potential Factors ◽

The Stability ◽

Major Factors ◽

The Impact ◽

Open Issues

The protein folded state is the result of the fine balance of a variety of different forces. Even minor structural perturbations may have a significant impact on the stability of these macromolecules. Studies carried out in recent decades have led to the convergent view that proteins are endowed with a flexible spine. One of the open issues related to protein local backbone geometry is the identification of the factors that influence the amplitude of the τ (N—Cα—C) angle. Here, statistical analyses performed on an updated ensemble of X-ray protein structures by dissecting the contribution of the major factors that can potentially influence the local backbone geometry of proteins are reported. The data clearly indicate that the local backbone conformation has a prominent impact on the modulation of the τ angle. Therefore, a proper assessment of the impact of the other potential factors can only be appropriately evaluated when small (φ, ψ) regions are considered. Here, it is shown that when the contribution of the backbone conformation is removed by considering small (φ, ψ) areas, an impact of secondary structure, as defined byDSSP, and/or the residue type on τ is still detectable, although to a limited extent. Indeed, distinct τ-value distributions are detected for Pro/Gly and β-branched (Ile/Val) residues. The key role of the local backbone conformation highlighted here supports the use of variable local backbone geometry in protein refinement protocols.

Download Full-text

The Impact of Pro-Inflammatory Cytokines on Alternative Splicing Patterns in Human Islets

Diabetes ◽

10.2337/db20-0847 ◽

2021 ◽

pp. db200847

Author(s):

Wenting Wu ◽

Farooq Syed ◽

Edward Simpson ◽

Chih-Chun Lee ◽

Jing Liu ◽

...

Keyword(s):

Alternative Splicing ◽

Inflammatory Cytokines ◽

Human Islets ◽

The Impact ◽

Splicing Patterns ◽

Pro Inflammatory Cytokines

Download Full-text

PB-kPRED: knowledge-based prediction of protein backbone conformation using a structural alphabet

10.1101/127423 ◽

2017 ◽

Author(s):

Iyanar Vetrivel ◽

Swapnil Mahajan ◽

Manoj Tyagi ◽

Lionel Hoffmann ◽

Yves-Henri Sanejouand ◽

...

Keyword(s):

Protein Structures ◽

Scoring Function ◽

Evolutionary Information ◽

Structural Alphabet ◽

Local Structures ◽

Knowledge Based ◽

Scanning Strategies ◽

Accuracy Of Prediction ◽

The Impact ◽

Protein Blocks

AbstractLibraries of structural prototypes that abstract protein local structures are known as structural alphabets and have proven to be very useful in various aspects of protein structure analyses and predictions. One such library, Protein Blocks (PBs), is composed of 16 standard 5-residues long structural prototypes. This form of analyzing proteins involves drafting its structure as a string of PBs. Thus, predicting the local structure of a protein in terms of protein blocks is a step towards the objective of predicting its 3-D structure. Here a new approach, kPred, is proposed towards this aim that is independent of the evolutionary information available. It involves (i) organizing the structural knowledge in the form of a database of pentapeptide fragments extracted from all protein structures in the PDB and (ii) apply a purely knowledge-based algorithm, not relying on secondary structure predictions or sequence alignment profiles, to scan this database and predict most probable backbone conformations for the protein local structures.Based on the strategy used for scanning the database, the method was able to achieve efficient mean Q16 accuracies between 40.8% and 66.3% for a non-redundant subset of the PDB filtered at 30% sequence identity cut-off. The impact of these scanning strategies on the prediction was evaluated and is discussed. A scoring function that gives a good estimate of the accuracy of prediction was further developed. This score estimates very well the accuracy of the algorithm (R2 of 0.82). An online version of the tool is provided freely for non-commercial usage at http://www.bo-protscience.fr/kpred/.

Download Full-text

Alternative Splicing of Transcription Factors' Genes: Beyond the Increase of Proteome Diversity

Comparative and Functional Genomics ◽

10.1155/2009/905894 ◽

2009 ◽

Vol 2009 ◽

pp. 1-6 ◽

Cited By ~ 11

Author(s):

David Talavera ◽

Modesto Orozco ◽

Xavier de la Cruz

Keyword(s):

Transcription Factors ◽

Alternative Splicing ◽

Expression Patterns ◽

Developmental Changes ◽

Functional Families ◽

Transcription Regulators ◽

Alternatively Spliced ◽

The Impact ◽

Human And Mouse

Functional modification of transcription regulators may lead to developmental changes and phenotypical differences between species. In this work, we study the influence of alternative splicing on transcription factors in human and mouse. Our results show that the impact of alternative splicing on transcription factors is similar in both species, meaning that the ways to increase variability should also be similar. However, when looking at the expression patterns of transcription factors, we observe that they tend to diverge regardless of the role of alternative splicing. Finally, we hypothesise that transcription regulation of alternatively spliced transcription factors could play an important role in the phenotypical differences between species, without discarding other phenomena or functional families.

Download Full-text