Increased intracellular Ca
            <sup>2+</sup>
            concentrations prevent membrane localization of PH domains through the formation of Ca
            <sup>2+</sup>
            -phosphoinositides

Kang, Jin Ku; Kim, Ok-Hee; Hur, June; Yu, So Hee; Lamichhane, Santosh; Lee, Jin Wook; Ojha, Uttam; Hong, Jeong Hee; Lee, Cheol Soon; Young, Jung Han; Lee, Young Jae; Im, Seung‐Soon; Park, Young Joo; Choi, Cheol Soo; Lee, Dong Hoon; Lee, Inkyu; Oh, Baek-Rock

doi:10.1073/pnas.1706489114

Cited by 41 publications

(46 citation statements)

References 46 publications

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“…A recent study of the PH domain of Akt kinase identified an unexpected role for Ca 2+ in inhibiting PtdIns(3,4,5)P 3 interaction and plasma membrane recruitment. Kang et al (2017) demonstrated that Ca 2+ can bind directly to di-and tri-phosphorylated phosphoinositide head groups at physiological concentrations leading to electrostatic inhibition of protein binding. It is likely that the same effect is causing the membrane dissociation we observe for the C2a C2C domain both in vitro and in cells, and this points to a wider role for Ca 2+ in negatively regulating protein-membrane association.…”

Section: Discussionmentioning

confidence: 99%

Molecular Basis for Membrane Recruitment by the PX and C2 Domains of Class II Phosphoinositide 3-Kinase-C2α

et al. 2018

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Phosphorylation of phosphoinositides by the class II phosphatidylinositol 3-kinase (PI3K) PI3K-C2a is essential for many processes, including neuroexocytosis and formation of clathrin-coated vesicles. A defining feature of the class II PI3Ks is a C-terminal module composed of phox-homology (PX) and C2 membrane interacting domains; however, the mechanisms that control their specific cellular localization remain poorly understood. Here we report the crystal structure of the C2 domain of PI3K-C2a in complex with the phosphoinositide head-group mimic inositol hexaphosphate, revealing two distinct pockets for membrane binding. The C2 domain preferentially binds to phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol (3,4,5)trisphosphate, and low-resolution structures of the combined PX-C2 module by small-angle X-ray scattering reveal a compact conformation in which cooperative lipid binding by each domain binding can occur. Finally, we demonstrate an unexpected role for calcium in perturbing the membrane interactions of the PX-C2 module, which we speculate may be important for regulating the activity of PI3K-C2a.

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Section: Discussionmentioning

confidence: 99%

Molecular Basis for Membrane Recruitment by the PX and C2 Domains of Class II Phosphoinositide 3-Kinase-C2α

et al. 2018

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“…Depending on the interaction with PI(4,5)P 2 , whether it is a receptor-ligand type of interaction such as a PLC␦PH domain or a pure electrostatic interaction such as MARCKS peptide, the net effect of Ca 2ϩ for a PI(4,5)P 2 -protein interaction might be different. The former has been investigated recently in both in vitro (34) and in cellular studies (18) in which the recognition of PI(4,5)P 2 by PLC␦PH domain was suppressed by Ca 2ϩ through forming Ca 2ϩ -PI(4,5)P 2 complexes. The latter case was investigated in this study by an actin assembly assay sensitive to actin nucleation-promoting factors that interact with PI(4,5)P 2 through an unstructured polybasic motif.…”

Section: Role Of Calciummentioning

confidence: 99%

Lateral distribution of phosphatidylinositol 4,5-bisphosphate in membranes regulates formin- and ARP2/3-mediated actin nucleation

Bucki

Wang

Yang³

et al. 2019

Journal of Biological Chemistry

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Edited by Alex TokerSpatial and temporal control of actin polymerization is fundamental for many cellular processes, including cell migration, division, vesicle trafficking, and response to agonists. Many actin-regulatory proteins interact with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) and are either activated or inactivated by local PI(4,5)P 2 concentrations that form transiently at the cytoplasmic face of cell membranes. The molecular mechanisms of these interactions and how the dozens of PI(4,5)P 2sensitive actin-binding proteins are selectively recruited to membrane PI(4,5)P 2 pools remains undefined. Using a combination of biochemical, imaging, and cell biologic studies, combined with molecular dynamics and analytical theory, we test the hypothesis that the lateral distribution of PI(4,5)P 2 within lipid membranes and native plasma membranes alters the capacity of PI(4,5)P 2 to nucleate actin assembly in brain and neutrophil extracts and show that activities of formins and the Arp2/3 complex respond to PI(4,5)P 2 lateral distribution. Simulations and analytical theory show that cholesterol promotes the cooperative interaction of formins with multiple PI(4,5)P 2 headgroups in the membrane to initiate actin nucleation. Masking PI(4,5)P 2 with neomycin or disrupting PI(4,5)P 2 domains in the plasma membrane by removing cholesterol decreases the ability of these membranes to nucleate actin assembly in cytoplasmic extracts.

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“…Interestingly, this pathway is specifically related to the experimental question, as research has shown that VEGFR2 can modulate insulin sensitivity in white adipose tissue [19]. However, the GSEA intersection approach identified the "Response to elevated platelet cytosolic Ca2+" Reactome pathway as having inverse changes, and Ca2+ has also been linked to regulation of insulin signaling [20]. Thus, the ECEA approach has some statistical advantages, but there are specific circumstances for which the GSEA intersection approach will work well.…”

Section: Discussionmentioning

confidence: 99%

Equivalent change enrichment analysis: assessing equivalent and inverse change in biological pathways between diverse experiments

Thompson

Koestler

2020

BMC Genomics

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Background: In silico functional genomics have become a driving force in the way we interpret and use gene expression data, enabling researchers to understand which biological pathways are likely to be affected by the treatments or conditions being studied. There are many approaches to functional genomics, but a number of popular methods determine if a set of modified genes has a higher than expected overlap with genes known to function as part of a pathway (functional enrichment testing). Recently, researchers have started to apply such analyses in a new way: to ask if the data they are collecting show similar disruptions to biological functions compared to reference data. Examples include studying whether similar pathways are perturbed in smokers vs. users of e-cigarettes, or whether a new mouse model of schizophrenia is justified, based on its similarity in cytokine expression to a previously published model. However, there is a dearth of robust statistical methods for testing hypotheses related to these questions and most researchers resort to ad hoc approaches. The goal of this work is to develop a statistical approach to identifying gene pathways that are equivalently (or inversely) changed across two experimental conditions. Results: We developed Equivalent Change Enrichment Analysis (ECEA). This is a new type of gene enrichment analysis based on a statistic that we call the equivalent change index (ECI). An ECI of 1 represents a gene that was over or under-expressed (compared to control) to the same degree across two experiments. Using this statistic, we present an approach to identifying pathways that are changed in similar or opposing ways across experiments. We compare our approach to current methods on simulated data and show that ECEA is able to recover pathways exhibiting such changes even when they exhibit complex patterns of regulation, which other approaches are unable to do. On biological data, our approach recovered pathways that appear directly connected to the condition being studied. Conclusions: ECEA provides a new way to perform gene enrichment analysis that allows researchers to compare their data to existing datasets and determine if a treatment will cause similar or opposing genomic perturbations.

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Increased intracellular Ca ²⁺ concentrations prevent membrane localization of PH domains through the formation of Ca ²⁺ -phosphoinositides

Cited by 41 publications

References 46 publications

Molecular Basis for Membrane Recruitment by the PX and C2 Domains of Class II Phosphoinositide 3-Kinase-C2α

Molecular Basis for Membrane Recruitment by the PX and C2 Domains of Class II Phosphoinositide 3-Kinase-C2α

Lateral distribution of phosphatidylinositol 4,5-bisphosphate in membranes regulates formin- and ARP2/3-mediated actin nucleation

Equivalent change enrichment analysis: assessing equivalent and inverse change in biological pathways between diverse experiments

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Increased intracellular Ca 2+ concentrations prevent membrane localization of PH domains through the formation of Ca 2+ -phosphoinositides

Cited by 41 publications

References 46 publications

Molecular Basis for Membrane Recruitment by the PX and C2 Domains of Class II Phosphoinositide 3-Kinase-C2α

Molecular Basis for Membrane Recruitment by the PX and C2 Domains of Class II Phosphoinositide 3-Kinase-C2α

Lateral distribution of phosphatidylinositol 4,5-bisphosphate in membranes regulates formin- and ARP2/3-mediated actin nucleation

Equivalent change enrichment analysis: assessing equivalent and inverse change in biological pathways between diverse experiments

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Increased intracellular Ca ²⁺ concentrations prevent membrane localization of PH domains through the formation of Ca ²⁺ -phosphoinositides