A Structural Model for Vinculin Insertion into PIP2-Containing Membranes and the Effect of Insertion on Vinculin Activation and Localization

Thompson, Peter M.; Ramachandran, Srinivas; Case, Lindsay B.; Tolbert, Caitlin E.; Tandon, Arpit; Pershad, Mihir; Dokholyan, Nikolay V.; Waterman, Clare M.; Campbell, Sharon L.

doi:10.1016/j.str.2016.12.002

Cited by 25 publications

(30 citation statements)

References 57 publications

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“…A dramatic reduction in binding to either PIP2 or PIP3 was observed for CDGIΔC1 compared with CDGI (Figure C), indicating a role of the C1 domain in PIP2/PIP3 recognition. Next, we compared the PIP2‐binding specificity between the isolated C1 domains of CDGI and CDGII, using the Vinculin tail (Vt) domain, a protein known to preferentially interact with PIP2 as a positive control. Although very limited co‐sedimentation with PIP2 was observed for the typical, DAG‐binding C1 domain of CDGII, co‐sedimentation of Vt and the C1 domain of CDGI demonstrated association with PIP2 (Figure D).…”

Section: Resultsmentioning

confidence: 99%

Subcellular localization of Rap1 GTPase activator CalDAG‐GEFI is orchestrated by interaction of its atypical C1 domain with membrane phosphoinositides

Sarker

Goliaei

Golesi

et al. 2020

Journal of Thrombosis and Haemostasis

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Background The small GTPase Rap1 and its guanine nucleotide exchange factor, CalDAG‐GEFI (CDGI), are critical for platelet function and hemostatic plug formation. CDGI function is regulated by a calcium binding EF hand regulatory domain and an atypical C1 domain with unknown function. Objective Here, we investigated whether the C1 domain controls CDGI subcellular localization, both in vitro and in vivo. Methods CDGI interaction with phosphoinositides was studied by lipid co‐sedimentation assays and molecular dynamics simulations. Cellular localization of CDGI was studied in heterologous cells by immunofluorescence and subcellular fractionation assays. Results Lipid co‐sedimentation studies demonstrated that the CDGI C1 domain associates with membranes through exclusive recognition of phosphoinositides, phosphatidylinositol (4,5)‐biphosphate (PIP2) and phosphatidylinositol (3,4,5)‐triphosphate (PIP3). Molecular dynamics simulations identified a phospholipid recognition motif consisting of residues exclusive to the CDGI C1 domain. Mutation of those residues abolished co‐sedimentation of the C1 domain with lipid vesicles and impaired membrane localization of CDGI in heterologous cells. Conclusion Our studies identify a novel interaction between an atypical C1 domain and phosphatidylinositol (4,5)‐biphosphate and phosphatidylinositol (3,4,5)‐triphosphate in cellular membranes, which is critical for Rap1 signaling in health and disease.

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Section: Resultsmentioning

confidence: 99%

Subcellular localization of Rap1 GTPase activator CalDAG‐GEFI is orchestrated by interaction of its atypical C1 domain with membrane phosphoinositides

Sarker

Goliaei

Golesi

et al. 2020

Journal of Thrombosis and Haemostasis

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“…Membrane bound talin recruits and activates vinculin. Vinculin localizes at the adhesion complex and interacts with PI(4,5)P2 to associate with the membrane 56 . Simulation data shows that PI(4,5)P2 is not required for vinculin localization at FAs but is needed for the activation of FA turnover during mechanotransduction processes 56 .…”

Section: Pip2 In Adhesion Dynamicsmentioning

confidence: 99%

“…Vinculin localizes at the adhesion complex and interacts with PI(4,5)P2 to associate with the membrane 56 . Simulation data shows that PI(4,5)P2 is not required for vinculin localization at FAs but is needed for the activation of FA turnover during mechanotransduction processes 56 . Other studies mentioned that PI(4,5)P2 is required for FA formation, and vinculin phosphorylation and trafficking 57 .…”

Section: Pip2 In Adhesion Dynamicsmentioning

confidence: 99%

Role of Phosphoinositides in Cellular Signaling, Functions and Diseases

Mandal¹

2020

Preprint

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In this review we summarize the recent development in understanding the role of PIP2 in cellular function and signaling. We first discuss the effect of PIP2 on actin binding proteins addressing the mechanism of the actin cytoskeletal dynamics such as polymerization or depolymerization of the filamentous network or the coupling to membrane to generate forces. Next, we outline the role of PIP2 in membrane dynamics. We summarized how the membrane organization depends upon PIP2 in the presence of ions or transmembrane proteins that are sensitive to membrane curvature. We discuss how clathrin coated pits interact with adaptor proteins during the endocytosis process, which is facilitated by PIP2. Finally, we discuss the role of PIP2 in cell signaling and diseases.

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“…IP3 is a key regulator of the cytoplasmic Ca 2+ concentration by controlling a Ca 2+ channel IP3 receptor on the endoplasmic reticulum (ER) . In addition to being the precursor of DAG and IP3, PI(4,5)P2 is also a key messenger that regulates the polymerization of the actin cytoskeleton, plasma membrane tension, exocytosis, membrane fusion, activity of ion channels, and cell adhesion, etc . Thus, PI(4,5)P2 is of great importance during receptor signaling and cell activation.…”

Section: Basic Roles Of Pi(45)p2 In Receptor Activationmentioning

confidence: 99%

A PI(4,5)P2‐derived “gasoline engine model” for the sustained B cell receptor activation

Wan

Shaheen

et al. 2019

Immunological Reviews

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To efficiently initiate activation responses against rare ligands in the microenvironment, lymphocytes employ sophisticated mechanisms involving signaling amplification. Recently, a signaling amplification mechanism initiated from phosphatidylinositol (PI) 4, 5‐biphosphate [PI(4,5)P2] hydrolysis and synthesis for sustained B cell activation has been reported. Antigen and B cell receptor (BCR) recognition triggered the prompt reduction of PI(4,5)P2 density within the BCR microclusters, which led to the positive feedback for the synthesis of PI(4,5)P2 outside of the BCR microclusters. At single molecule level, the diffusion of PI(4,5)P2 was slow, allowing for the maintenance of a PI(4,5)P2 density gradient between the inside and outside of the BCR microclusters and the persistent supply of PI(4,5)P2 from outside to inside of the BCR microclusters. Here, we review studies that have contributed to uncovering the molecular mechanisms of PI(4,5)P2‐derived signaling amplification model. Based on these studies, we proposed a “gasoline engine model” in which the activation of B cell signaling inside the microclusters is similar to the working principle of burning gasoline within the engine chamber of a gasoline engine. We also discuss the evidences showing the potential universality of this model and future prospects.

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A Structural Model for Vinculin Insertion into PIP2-Containing Membranes and the Effect of Insertion on Vinculin Activation and Localization

Cited by 25 publications

References 57 publications

Subcellular localization of Rap1 GTPase activator CalDAG‐GEFI is orchestrated by interaction of its atypical C1 domain with membrane phosphoinositides

Subcellular localization of Rap1 GTPase activator CalDAG‐GEFI is orchestrated by interaction of its atypical C1 domain with membrane phosphoinositides

Role of Phosphoinositides in Cellular Signaling, Functions and Diseases

A PI(4,5)P2‐derived “gasoline engine model” for the sustained B cell receptor activation

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