Inositol Pyrophosphate Pathways and Mechanisms: What Can We Learn from Plants?

The ability of an organism to maintain homeostasis in changing conditions is crucial for growth and survival. Eukaryotes have developed complex signaling pathways to adapt to a readily changing environment, including the inositol phosphate (InsP) signaling pathway. In plants and humans the pyrophosphorylated inositol molecules, inositol pyrophosphates (PP-InsPs), have been implicated in phosphate and energy sensing. PP-InsPs are synthesized from the phosphorylation of InsP6, the most abundant InsP. The plant PP-InsP synthesis pathway is similar but distinct from that of the human, which may reflect differences in how molecules such as Ins(1,4,5)P3 and InsP6 function in plants vs. animals. In addition, PP-InsPs can potentially interact with several major signaling proteins in plants, suggesting PP-InsPs play unique signaling roles via binding to protein partners. In this review, we will compare the biosynthesis and role of PP-InsPs in animals and plants, focusing on three central themes: InsP6 synthesis pathways, synthesis and regulation of the PP-InsPs, and function of a specific protein domain called the Syg1, Pho1, Xpr1 (SPX ) domain in binding PP-InsPs and regulating inorganic phosphate (Pi) sensing. This review will provide novel insights into the biosynthetic pathway and bioactivity of these key signaling molecules in plant and human systems.

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Novel Substrates for Kinases Involved in the Biosynthesis of Inositol Pyrophosphates and Their Enhancement of ATPase Activity of a Kinase

Molecules ◽

10.3390/molecules26123601 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3601

Author(s):

Raja Mohanrao ◽

Ruth Manorama ◽

Shubhra Ganguli ◽

Mithun C. Madhusudhanan ◽

Rashna Bhandari ◽

...

Keyword(s):

Enzyme Activity ◽

Atpase Activity ◽

Catalytic Domain ◽

Inositol Phosphate ◽

Substrate Recognition ◽

Competitive Inhibitor ◽

Inositol Polyphosphates ◽

Inositol Pyrophosphate ◽

Phosphate Donor ◽

Inositol Pyrophosphates

IP6K and PPIP5K are two kinases involved in the synthesis of inositol pyrophosphates. Synthetic analogs or mimics are necessary to understand the substrate specificity of these enzymes and to find molecules that can alter inositol pyrophosphate synthesis. In this context, we synthesized four scyllo-inositol polyphosphates—scyllo-IP5, scyllo-IP6, scyllo-IP7 and Bz-scyllo-IP5—from myo-inositol and studied their activity as substrates for mouse IP6K1 and the catalytic domain of VIP1, the budding yeast variant of PPIP5K. We incubated these scyllo-inositol polyphosphates with these kinases and ATP as the phosphate donor. We tracked enzyme activity by measuring the amount of radiolabeled scyllo-inositol pyrophosphate product formed and the amount of ATP consumed. All scyllo-inositol polyphosphates are substrates for both the kinases but they are weaker than the corresponding myo-inositol phosphate. Our study reveals the importance of axial-hydroxyl/phosphate for IP6K1 substrate recognition. We found that all these derivatives enhance the ATPase activity of VIP1. We found very weak ligand-induced ATPase activity for IP6K1. Benzoyl-scyllo-IP5 was the most potent ligand to induce IP6K1 ATPase activity despite being a weak substrate. This compound could have potential as a competitive inhibitor.

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Chemical tools for interrogating inositol pyrophosphate structure and function

Chemical Society Reviews ◽

10.1039/c6cs00193a ◽

2016 ◽

Vol 45 (22) ◽

pp. 6311-6326 ◽

Cited By ~ 18

Author(s):

Nathaniel W. Brown ◽

Alan M. Marmelstein ◽

Dorothea Fiedler

Keyword(s):

Structure And Function ◽

Intracellular Metabolites ◽

Inositol Pyrophosphate ◽

Inositol Pyrophosphates ◽

Chemical Tools ◽

Eukaryotic Organisms ◽

And Function ◽

Analytical Tools

New chemical and analytical tools have been developed to study the diverse functions of the inositol pyrophosphates, a unique group of densely phosphorylated intracellular metabolites found in a wide variety of eukaryotic organisms.

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Interaction of Plasmodium falciparum apicortin with α- and β-tubulin is critical for parasite growth and survival

Scientific Reports ◽

10.1038/s41598-021-83513-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Malabika Chakrabarti ◽

Nishant Joshi ◽

Geeta Kumari ◽

Preeti Singh ◽

Rumaisha Shoaib ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Life Cycle ◽

Specific Protein ◽

Parasite Growth ◽

Growth And Survival ◽

Apicomplexan Parasites ◽

Parasite Replication ◽

Main Components ◽

Β Tubulin

AbstractCytoskeletal structures of Apicomplexan parasites are important for parasite replication, motility, invasion to the host cell and survival. Apicortin, an Apicomplexan specific protein appears to be a crucial factor in maintaining stability of the parasite cytoskeletal assemblies. However, the function of apicortin, in terms of interaction with microtubules still remains elusive. Herein, we have attempted to elucidate the function of Plasmodium falciparum apicortin by monitoring its interaction with two main components of parasite microtubular structure, α-tubulin-I and β-tubulin through in silico and in vitro studies. Further, a p25 domain binding generic drug Tamoxifen (TMX), was used to disrupt PfApicortin-tubulin interactions which led to the inhibition in growth and progression of blood stage life cycle of P. falciparum.

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Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

Current Medicinal Chemistry ◽

10.2174/0929867324666170426095015 ◽

2018 ◽

Vol 25 (1) ◽

pp. 5-21 ◽

Cited By ~ 25

Author(s):

Ylenia Cau ◽

Daniela Valensin ◽

Mattia Mori ◽

Sara Draghi ◽

Maurizio Botta

Keyword(s):

Protein Interactions ◽

Molecular Mechanisms ◽

Physiological Role ◽

Specific Protein ◽

Protein Protein Interactions ◽

Cellular Processes ◽

Protein Partners ◽

High Sequence Homology ◽

Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

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Novel Roles of SH2 and SH3 Domains in Lipid Binding

Cells ◽

10.3390/cells10051191 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1191

Author(s):

Szabolcs Sipeki ◽

Kitti Koprivanacz ◽

Tamás Takács ◽

Anita Kurilla ◽

Loretta László ◽

...

Keyword(s):

Protein Interactions ◽

Specific Protein ◽

Lipid Binding ◽

Sh2 Domain ◽

Essential Property ◽

Cellular Regulation ◽

Sh3 Domains ◽

Protein Partners ◽

Interaction Domains ◽

Central Paradigm

Signal transduction, the ability of cells to perceive information from the surroundings and alter behavior in response, is an essential property of life. Studies on tyrosine kinase action fundamentally changed our concept of cellular regulation. The induced assembly of subcellular hubs via the recognition of local protein or lipid modifications by modular protein interactions is now a central paradigm in signaling. Such molecular interactions are mediated by specific protein interaction domains. The first such domain identified was the SH2 domain, which was postulated to be a reader capable of finding and binding protein partners displaying phosphorylated tyrosine side chains. The SH3 domain was found to be involved in the formation of stable protein sub-complexes by constitutively attaching to proline-rich surfaces on its binding partners. The SH2 and SH3 domains have thus served as the prototypes for a diverse collection of interaction domains that recognize not only proteins but also lipids, nucleic acids, and small molecules. It has also been found that particular SH2 and SH3 domains themselves might also bind to and rely on lipids to modulate complex assembly. Some lipid-binding properties of SH2 and SH3 domains are reviewed here.

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Phylogenetic Comparison and Splicing Analysis of the U1 snRNP-specific Protein U1C in Eukaryotes

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.696319 ◽

2021 ◽

Vol 8 ◽

Author(s):

Kai-Lu Zhang ◽

Jian-Li Zhou ◽

Jing-Fang Yang ◽

Yu-Zhen Zhao ◽

Debatosh Das ◽

...

Keyword(s):

Gene Family ◽

Cancer Progression ◽

Expression Profiles ◽

Expression Patterns ◽

Specific Protein ◽

Comprehensive Overview ◽

Small Nuclear Ribonucleoprotein ◽

U1 Snrnp ◽

Multiple Copies ◽

And Function

As a pivotal regulator of 5’ splice site recognition, U1 small nuclear ribonucleoprotein (U1 snRNP)-specific protein C (U1C) regulates pre-mRNA splicing by interacting with other components of the U1 snRNP complex. Previous studies have shown that U1 snRNP and its components are linked to a variety of diseases, including cancer. However, the phylogenetic relationships and expression profiles of U1C have not been studied systematically. To this end, we identified a total of 110 animal U1C genes and compared them to homologues from yeast and plants. Bioinformatics analysis shows that the structure and function of U1C proteins is relatively conserved and is found in multiple copies in a few members of the U1C gene family. Furthermore, the expression patterns reveal that U1Cs have potential roles in cancer progression and human development. In summary, our study presents a comprehensive overview of the animal U1C gene family, which can provide fundamental data and potential cues for further research in deciphering the molecular function of this splicing regulator.

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Intrinsically disordered proteins identified in the aggregate proteome serve as biomarkers of neurodegeneration

Metabolic Brain Disease ◽

10.1007/s11011-021-00791-8 ◽

2021 ◽

Author(s):

Srinivas Ayyadevara ◽

Akshatha Ganne ◽

Meenakshisundaram Balasubramaniam ◽

Robert J. Shmookler Reis

Keyword(s):

Intrinsically Disordered Proteins ◽

Protein Complexes ◽

Disordered Proteins ◽

Intrinsically Disordered ◽

Intrinsically Disordered Regions ◽

Physiological Processes ◽

Protein Partners ◽

And Function ◽

Computational Analyses ◽

Disordered Regions

AbstractA protein’s structure is determined by its amino acid sequence and post-translational modifications, and provides the basis for its physiological functions. Across all organisms, roughly a third of the proteome comprises proteins that contain highly unstructured or intrinsically disordered regions. Proteins comprising or containing extensive unstructured regions are referred to as intrinsically disordered proteins (IDPs). IDPs are believed to participate in complex physiological processes through refolding of IDP regions, dependent on their binding to a diverse array of potential protein partners. They thus play critical roles in the assembly and function of protein complexes. Recent advances in experimental and computational analyses predicted multiple interacting partners for the disordered regions of proteins, implying critical roles in signal transduction and regulation of biological processes. Numerous disordered proteins are sequestered into aggregates in neurodegenerative diseases such as Alzheimer’s disease (AD) where they are enriched even in serum, making them good candidates for serum biomarkers to enable early detection of AD.

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Ubiquitin-dependent regulation of a conserved DMRT protein controls sexually dimorphic synaptic connectivity and behavior

eLife ◽

10.7554/elife.59614 ◽

2020 ◽

Vol 9 ◽

Author(s):

Emily A Bayer ◽

Rebecca C Stecky ◽

Lauren Neal ◽

Phinikoula S Katsamba ◽

Goran Ahlsen ◽

...

Keyword(s):

Specific Protein ◽

Protein Stabilization ◽

Protein Domain ◽

Synaptic Connectivity ◽

Sexually Dimorphic ◽

Posttranslational Regulation ◽

Neuronal Function ◽

Related Transcription Factor ◽

Sex Specificity ◽

And Behavior

Sex-specific synaptic connectivity is beginning to emerge as a remarkable, but little explored feature of animal brains. We describe here a novel mechanism that promotes sexually dimorphic neuronal function and synaptic connectivity in the nervous system of the nematode Caenorhabditis elegans. We demonstrate that a phylogenetically conserved, but previously uncharacterized Doublesex/Mab-3 related transcription factor (DMRT), dmd-4, is expressed in two classes of sex-shared phasmid neurons specifically in hermaphrodites but not in males. We find dmd-4 to promote hermaphrodite-specific synaptic connectivity and neuronal function of phasmid sensory neurons. Sex-specificity of DMD-4 function is conferred by a novel mode of posttranslational regulation that involves sex-specific protein stabilization through ubiquitin binding to a phylogenetically conserved but previously unstudied protein domain, the DMA domain. A human DMRT homolog of DMD-4 is controlled in a similar manner, indicating that our findings may have implications for the control of sexual differentiation in other animals as well.

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