TAPAS-1, a Novel Microdomain within the Unique N-terminal Region of the PDE4A1 cAMP-specific Phosphodiesterase That Allows Rapid, Ca2+-triggered Membrane Association with Selectivity for Interaction with Phosphatidic Acid

Abstract

Here we identify an 11-residue helical module in the unique N-terminal region of the cyclic AMP-specific phosphodiesterase PDE4A1 that determines association with phospholipid bilayers and shows a profound selectivity for interaction with phosphatidic acid (PA It is becoming increasingly recognized that the compartmentalization of proteins within specific regions of the cell is pivotal to the appropriate functioning of many, if not all, signaling pathways. For example, the localization of the RII subunits of PKA 1 to distinct intracellular sites, achieved by binding to A-Kinase-Anchor Proteins (AKAPs), allows for the localized activation of this protein kinase and functionally compartmentalized signaling (1). Activation of signaling processes themselves can lead to changes in the organization of intracellular proteins. This can take the form of protein-protein interactions, of which the SH2 and SH3 modules provide mechanistic and structural examples (2, 3). However, more recently, lipid-directed re-organization of protein components within cells has been recognized, such as that seen in the binding of phosphoinositides to pleckstrin homology (PH) and FYVE domain modules, as well as the interaction of C2 domains with phospholipids (4, 5). To appreciate the ways in which various signaling processes are connected in the cell, it is important to appreciate the range of protein modules that allow for interaction with intracellular anchors.Stimulation of many cells with a plethora of growth factors, cytokines, and hormones activates phospholipase D (PLD). This enzyme catalyzes the hydrolysis of phosphatidylcholine to generate phosphatidic acid (PA) which is presumed to mediate downstream signaling effects such as secretion, vesicle trafficking, cytoskeletal reorganization, apoptosis, and mitogenesis (6 -8). PA has been reported to bind to and activate Raf-1, and a neutrophil PA-regulated protein kinase has been described (9, 10). In addition, PA has been shown to activate "long form" cAMP phosphodiesterases (11)(12)(13)(14). However, how PA specifically interacts with signaling proteins is not yet clear. In particular, no module akin to either the pleckstrin homology or the FYVE domains involved in selectively binding 3-phosphorylated phosphoinositides or the C2 domains that are able to bind

Subcellular Localization of Cyclic Nucleotide Phosphodiesterase Type 10A Variants, and Alteration of the Localization by cAMP-dependent Protein Kinase-dependent Phosphorylation

“…Many splice variants of PDEs, other than PDE10A, having unique amino and carboxyl termini show distinct subcellular localization (17,23,25,39). We demonstrated here that PDE10A2 was predominantly present in membrane fractions of transiently transfected PC12h cells.…”

“…Myomegalin, a soluble fragment of AKAP450, and muscle-selective AKAP were identified as anchoring proteins of PDE4D to the Golgi/ centrosomal region (30,31,40). More recently, tryptophananchoring phosphatidic acid-selective binding domain 1 of PDE4A1 was demonstrated to be associated with phosphatidic acid of plasma membrane (39). PDE10A2 has no transmembrane domain in its unique amino-terminal region.…”

Antineutrophil Cytoplasm Antibody–Stimulated Neutrophil Adhesion Depends on Diacylglycerol Kinase–Catalyzed Phosphatidic Acid Formation

“…However, it is apparent that the PtdOH that is generated by this reaction can have a signaling role, and a number of studies have pointed to important roles for this pathway, with PtdOH able to activate a number of enzymes in signaling cascades such as phosphatidylinositol 4-phosphate 5-kinase (18), cAMP phosphodiesterase 4A1 (19), and sphingosine kinase (20). The DG kinases are a multigene family of enzymes that are subdivided into five classes with differing regulation and apparent regulatory functions (17).…”

Protein–protein interactions of PDE4 family members — Functions, interactions and therapeutic value

“…PDEs are the sole means for cAMP degradation and prevent its uniform cellular distribution as they are strategically positioned and thereby establish gradients of cAMP that are sensed by its effectors. PDEs are tethered to subcellular compartments through direct association with membranes [5,6], or through interactions with proteins that direct them to defined compartments. Protein binding partners include scaffolding proteins such as the A-kinase anchoring proteins (AKAPs), a heterogeneous family of around 50 proteins characterised by their common ability to directly interact with PKA [7,8].…”