Trends in Biochemical Sciences
ReviewShaping up the membrane: diacylglycerol coordinates spatial orientation of signaling
Section snippets
Half a century of diacylglycerol research
Since the initial characterization, over four decades ago, of receptor-dependent inositol phospholipid hydrolysis, the generation of a diacylglycerol (DAG) pool with signaling properties has been one of the best-studied models of receptor-regulated signaling. The identification of the protein kinase C (PKC) family as DAG-regulated kinases, and later as receptors for the tumor-promoting DAG analog phorbol ester (PE), intensified the search for DAG-based mechanisms. Studies over the years
The where and when of DAG: C1 domains as bioprobes
Decoding DAG signals in the cell requires the structurally conserved protein kinase C type I (C1) domains, whose α-helix and two antiparallel β-sheets form two flexible loops that generate a binding pocket into which the lipid is inserted. Originally described as a conserved region responsible for allosteric activation of PKC isozymes, C1 domains are found in other DAG effector proteins, including PKD, chimaerins, Unc13 and RasGRP. Non-DAG-binding ‘atypical’ C1 domains are found in some
The immune synapse: a polarized site of DAG action
IS formation between T cells and APCs is a clear example of DAG function in signaling, polarization and trafficking. Large morphological changes are produced in T cells during synapse formation. After specific antigen recognition, the T cell receptor (TCR) is activated and organizes a structured signaling platform, with extensive membrane remodeling and organelle reorganization; the secretory machinery, Golgi apparatus, microtubule-organizing center (MTOC) and mitochondria then polarize towards
DAG function in the neuronal synapse: both sides of the story
Neurons are highly structured cells, divided morphologically into a presynaptic area at the axon terminals and a postsynaptic area with dendrite spines; in a secretory synapse, the former specialize in neurotransmitter secretion, whereas the latter is enriched in receptors and signal transduction proteins [18] (Figure 3b). Communication between these areas establishes continuous structural modifications, weakening or strengthening contacts and allowing synapse plasticity. This is especially
Phagocytosis: linking membrane remodeling to effector signals
During phagocytosis, cells of the innate immune system (macrophages and neutrophils) engulf invading pathogens and apoptotic bodies. Promoted by various receptors (Fc, complement, mannose and lipopolysaccharide (LPS) receptors, as well as integrins), phagocytic cells create an extended pseudopod to provide a membrane area where the nascent phagosome will be generated [47]. Lipids participate in both processes by governing membrane remodeling and triggering signaling pathways important for
C1 domains: playing hide-and-seek
Although C1 motifs share considerable similarity between DAG-responding proteins, alterations in their sequences confer differences in affinity, penetration and membrane specificity, which regulate their activation mechanisms 3, 59. DAG responses are controlled at several levels. At the secondary structural level, groove accessibility might be sterically impeded in the C1 motif, necessitating greater conformational change for DAG insertion; this is the case of the Munc13 C1 domain, in which a
Concluding remarks
Our knowledge of diacylglycerol metabolism and function has expanded greatly since its initial characterization as the PKC allosteric modulator. The original concept of DAG as a transient recruiter of protein kinases to the plasma membrane has evolved to a complex picture in which DAG generation and consumption delimits ‘hot’ areas in the cell where secretion, receptor endocytosis, cytoskeletal reorganization and protein phosphorylation act in coordination.
The large scaffolds where
Acknowledgments
We sincerely apologize to all those authors whose work cannot be cited here owing to space limitations. We thank Drs Severine Gharbi, Mar Valés, Hugh Reyburn and Manuel Izquierdo for critical reading and comment, and Catherine Mark for excellent editorial assistance. M.A. is a recipient of a fellowship from the Madrid Regional Government. Work in the author's laboratory is supported by grants from the Spanish Ministry of Health (Instituto de Salud Carlos III; RD067002071035), the Spanish
References (95)
- et al.
Diacylglycerol, when simplicity becomes complex
Trends Biochem. Sci.
(2007) - et al.
C1 domains exposed: from diacylglycerol binding to protein-protein interactions
Biochim. Biophys. Acta
(2006) Diacylglycerol and protein kinase D localization during T lymphocyte activation
Immunity
(2006)- et al.
Calcium transduces plasma membrane receptor signals to produce diacylglycerol at Golgi membranes
J. Biol. Chem.
(2010) Signal strength in thymic selection and lineage commitment
Curr. Opin. Immunol.
(2001)Proteomics identification of sorting nexin 27 as a diacylglycerol kinase zeta-associated protein: new diacylglycerol kinase roles in endocytic recycling
Mol. Cell Proteomics
(2007)- et al.
Presynaptic signal transduction pathways that modulate synaptic transmission
Curr. Opin. Neurobiol.
(2009) - et al.
Modulation of neurotransmitter release by the second messenger-activated protein kinases: implications for presynaptic plasticity
Pharmacol. Ther.
(2005) Beta phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs
Cell
(2002)- et al.
Essential role for the PKC target MARCKS in maintaining dendritic spine morphology
Neuron
(2005)