Phospholipase C (PLC) is a receptor-regulated enzyme that hydrolyses phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) at the plasma membrane (PM) triggering three biochemical consequences, the generation of soluble inositol 1,4,5-trisphosphate (IP3), membrane-associated diacylglycerol (DG) and the consumption of PM PI(4,5)P2. Each of these three signals triggers multiple molecular processes impacting key cellular properties. The activation of PLC also triggers a sequence of biochemical reactions, collectively referred to as the PI(4,5)P2 cycle that culminates in the resynthesis of this lipid. The biochemical intermediates of this cycle and the enzymes that mediate these reactions are topologically distributed across two membrane compartments, the PM and the endoplasmic reticulum (ER). At the PM, the DG formed during PLC activation is rapidly converted into phosphatidic acid (PA) that needs to be transported to the ER where the machinery for its conversion into PI is localised. Conversely, PI from the ER needs to be rapidly transferred to the PM where it can be phosphorylated by lipid kinases to regenerate PI(4,5)P2. Thus, two lipid transport steps between membrane compartments through the cytosol are required for the replenishment of PI(4,5)P2 at the PM. Here, we review the topological constraints in the PI(4,5)P2 cycle and current understanding how these constraints are overcome during PLC signalling. In particular, we discuss the role of lipid transfer proteins in this process. Recent findings on the biochemical properties of a membrane-associated lipid transfer protein of the PITP family, PITPNM proteins (alternative name RdgBα/Nir proteins) that localise to membrane contact sites are discussed. Studies in both Drosophila and mammalian cells converge to provide a resolution to the conundrum of reciprocal transfer of PA and PI during PLC signalling.
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December 2016
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Structure of the C-terminal part of C. elegans cyclase-associated protein (CAS-2) (top) was modeled as a dimer based on the structure of the C-terminal part of human CAP1 (bottom). Mutagenesis study revealed an essential role of the C-terminal dimerization motif for the actin-regulatory activities of CAS-2. Please see pp. 4427–4441 for further information. Image provided by S. Ono.
Review Article|
November 25 2016
Topological organisation of the phosphatidylinositol 4,5-bisphosphate–phospholipase C resynthesis cycle: PITPs bridge the ER–PM gap
Shamshad Cockcroft;
Shamshad Cockcroft
1Department of Neuroscience, Physiology and Pharmacology, Division of Biosciences, University College London, London WC1E 6JJ, U.K.;
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Padinjat Raghu
Padinjat Raghu
2National Centre for Biological Sciences, TIFR-GKVK Campus, Bellary Road, Bangalore 560065, India
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Publisher: Portland Press Ltd
Received:
May 27 2016
Revision Received:
September 08 2016
Accepted:
September 12 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (23): 4289–4310.
Article history
Received:
May 27 2016
Revision Received:
September 08 2016
Accepted:
September 12 2016
Citation
Shamshad Cockcroft, Padinjat Raghu; Topological organisation of the phosphatidylinositol 4,5-bisphosphate–phospholipase C resynthesis cycle: PITPs bridge the ER–PM gap. Biochem J 1 December 2016; 473 (23): 4289–4310. doi: https://doi.org/10.1042/BCJ20160514C
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