The active site of yeast phosphatidylinositol synthase Pis1 is facing the cytosol

Bochud, Arlette; Conzelmann, Andreas

doi:10.1016/j.bbalip.2015.02.006

Cited by 11 publications

(13 citation statements)

References 34 publications

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“…PLC makes DAG and this undergoes five modifications to be returned to PI(4,5)P2 (Figure 1). But the second and third of these modifications are carried out by ER membrane enzymes [12,13], the active sites of which are located in short (≤20 aa) loops on their cytosolic faces. Therefore, plasma membrane lipids ≥15 nm away [14•] cannot be substrates.…”

Section: Ca 2+ Signaling At the Plasma Membrane And The Phosphatidylimentioning

confidence: 99%

Signalling at membrane contact sites: two membranes come together to handle second messengers

Levine¹,

Patel

2016

Current Opinion in Cell Biology

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It is now clear that many intracellular signals result from multiple membrane-bound compartments acting in concert. Membrane contact sites, regions of close apposition between organelles, have emerged as major points of convergence during signalling, as these are places where material is exchanged. The material exchanged can be either water-insoluble molecules such as membrane lipids that are passed directly between organelles, or ions such as Ca(2+). Here we highlight new insights into the role of contacts in signalling by second messengers, including lipid traffic that underpins re-generation of IP3, the regulation of NAADP and store-operated Ca(2+) signals, and possible involvement in cyclic AMP signalling.

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Section: Ca 2+ Signaling At the Plasma Membrane And The Phosphatidylimentioning

confidence: 99%

Signalling at membrane contact sites: two membranes come together to handle second messengers

Levine¹,

Patel

2016

Current Opinion in Cell Biology

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“…PI is synthesized on the cytosolic face of the ER (Bochud and Conzelmann, 2015), from where some is “flopped” to the luminal leaflet for the synthesis of glycosylphosphatidylinositol-linked proteins (Vishwakarma et al, 2005). The remaining PI has been shown to be distributed fairly evenly across most organelle membranes by sub-cellular fractionation (Vance, 2015).…”

Section: Introductionmentioning

confidence: 99%

Probing the Subcellular Distribution of Phosphatidylinositol Reveals a Surprising Lack at the Plasma Membrane

Zewe

Miller

Sangappa

et al. 2019

Preprint

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Zewe et al develop approaches to map the subcellular distribution of the major 14 phospholipid, phosphatidylinositol (PI), revealing that the lipid is present in most membranes 15 except for plasma membrane, where it is mainly found as PI4P and PI(4,5)P2. 16Abstract 1 The polyphosphoinositides (PPIn) are central regulatory lipids that direct membrane function in 2 eukaryotic cells. Understanding how their synthesis is regulated is crucial to revealing these 3 lipids' role in health and disease. PPIn are derived from the major structural lipid, 4 phosphatidylinositol (PI). However, although the distribution of most PPIn have been 5 characterized, the subcellular localization of PI available for PPIn synthesis is not known. Here, 6 we have used several orthogonal approaches to map the subcellular distribution of PI, including 7 localizing exogenous fluorescent PI, as well as detecting lipid conversion products of 8 endogenous PI after acute chemogenetic activation of PI-specific phospholipase and 4-kinase. 9We report that PI is broadly distributed throughout intracellular membrane compartments. 10However, there is a surprising lack of PI in the plasma membrane compared to the PPIn. These 11 experiments implicate regulation of PI supply to the plasma membrane, as opposed to 12 regulation of PPIn-kinases, as crucial to the control of PPIn synthesis and function at the PM.

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“…Early subcellular fractionation and reconstitution experiments suggested that the active site of Pis1 may face the cytosol [64,82]. Very recently, by introducing cysteine residues at various positions in the primary sequence of S. cerevisiae Pis1 and monitoring their accessibility to alkylating reagents, the cytosolic location of the active site was confirmed [83] (Figure 7). In addition, an active site facing the cytosol is in line with modeling studies of Pis1 based on the crystal structures of A. fulgidus CDP-alcohol-phosphotransferases (see above) [83,84].…”

Section: Subcellular Location and Membrane Topology Of Phosphatidylinmentioning

confidence: 99%

“…Very recently, by introducing cysteine residues at various positions in the primary sequence of S. cerevisiae Pis1 and monitoring their accessibility to alkylating reagents, the cytosolic location of the active site was confirmed [83] (Figure 7). In addition, an active site facing the cytosol is in line with modeling studies of Pis1 based on the crystal structures of A. fulgidus CDP-alcohol-phosphotransferases (see above) [83,84]. In mammalian cells, PI synthase was originally found in a mitochondrial fraction from kidney cells [85] and the ER in rat lung pneumocytes [86,87].…”

Section: Subcellular Location and Membrane Topology Of Phosphatidylinmentioning

confidence: 99%

“…In retrospective, these observations can now be explained by the sub-cellular localization and topology of PI synthase in these organisms (Figure 7): the active site of ER-bound yeast Pis1 faces the cytosol and, thus, can incorporate myo -[ 3 H]inositol taken up from the environment as substrate for GPI synthesis in the ER. In contrast, T. brucei PI synthase is localized in both the ER and Golgi [83], with the active site facing the lumen. The ER enzyme provides PI for GPI synthesis, using de novo synthesized myo -inositol, whereas the Golgi enzyme uses exogenous myo -[ 3 H]inositol for bulk PI, but not GPI, synthesis after its TbHMIT-mediated transport into the lumen of the Golgi.…”

Section: Subcellular Location and Membrane Topology Of Phosphatidylinmentioning

confidence: 99%

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Lipid topogenesis — 35 years on

Chauhan

Farine

Pandey

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Glycerophospholipids are the principal fabric of cellular membranes. The pathways by which these lipids are synthesized were elucidated mainly through the work of Kennedy and colleagues in the late 1950s and early 1960s. Subsequently, attention turned to cell biological aspects of lipids: Where in the cell are lipids synthesized? How are lipids integrated into membranes to form a bilayer? How are they sorted and transported from their site of synthesis to other cellular destinations? These topics, collectively termed ‘lipid topogenesis’, were the subject of a review article in 1981 by Bell, Ballas and Coleman. We now assess what has been learned about early events of lipid topogenesis, i.e. “lipid synthesis, the integration of lipids into membranes, and lipid translocation across membranes”, in the 35 years since the publication of this important review. We highlight the recent elucidation of the X-ray structures of key membrane enzymes of glycerophospholipid synthesis, progress on identifying lipid scramblase proteins needed to equilibrate lipids across membranes, and new complexities in the subcellular location and membrane topology of phosphatidylinositol synthesis revealed through a comparison of two unicellular model eukaryotes.

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The active site of yeast phosphatidylinositol synthase Pis1 is facing the cytosol

Cited by 11 publications

References 34 publications

Signalling at membrane contact sites: two membranes come together to handle second messengers

Signalling at membrane contact sites: two membranes come together to handle second messengers

Probing the Subcellular Distribution of Phosphatidylinositol Reveals a Surprising Lack at the Plasma Membrane

Lipid topogenesis — 35 years on

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