ArticleJournal of thrombosis and haemostasis : JTH2020
Subcellular localization of Rap1 GTPase activator CalDAG-GEFI is orchestrated by interaction of its atypical C1 domain with membrane phosphoinositides.
Article in Journal of thrombosis and haemostasis : JTH, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
What it found
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Who cites it
5 citing papers in PubMed.
- Differential Lipid Binding Specificities of RAP1A and RAP1B are Encoded by the Amino Acid Sequence of the Membrane Anchors.Journal of the American Chemical Society · 2024Article
- Molecular basis and cellular functions of vinculin-actin directional catch bonding.Nature communications · 2023Article
- CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors.Neurobiology of disease · 2021Article
- Integration of Rap1 and Calcium Signaling.International journal of molecular sciences · 2020Review
- RasGRP2 Structure, Function and Genetic Variants in Platelet Pathophysiology.International journal of molecular sciences · 2020Review
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
backgroundThe 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.
objectiveHere, we investigated whether the C1 domain controls CDGI subcellular localization, both in vitro and in vivo.
methodsCDGI 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.
resultsLipid 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.
conclusionOur 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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