Phospholipid Scramblase: When Phospholipid Asymmetry Goes Away

Bevers, Edouard M.; Williamson, Patrick

doi:10.1002/9781118120118.ch7

Cited by 2 publications

(1 citation statement)

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“…As lipids travel from the ER to the plasma membrane through the Golgi apparatus, the lipid composition of the membranes becomes progressively asymmetric via the action of two classes of ATP-driven enzymes, flippases and floppases, which catalyze the slow transbilayer movement of lipids between leaflets and establish their chemical gradients (Balasubramanian and Schroit, 2003; Pomorski and Menon, 2006; Bevers and Williamson, 2010). The final result of their activity is the generation and maintenance of strict lipid asymmetry in the plasma membrane: choline-containing phospholipids, phosphatidylcholine (PC), and sphingomyelin, are more abundant in the outer leaflet whereas amino phospholipids, phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphoinositides (such as PI and PIP 2 ), are confined to the inner leaflet (Holthuis and Levine, 2005; Bevers and Williamson, 2010, 2011). Flippases and floppases are lipid-specific, with the former mostly belonging to the P4 subfamily of ATPases tasked with the internalization of PE and PS, whereas the latter are ATP-binding cassette transporters and move PC and sphingomyelin from the inner to the outer leaflet (Seigneuret and Devaux, 1984; Pomorski and Menon, 2006; Quazi and Molday, 2013).…”

Section: Introductionmentioning

confidence: 99%

Known structures and unknown mechanisms of TMEM16 scramblases and channels

Falzone

Malvezzi

Lee

et al. 2018

Journal of General Physiology

102

109

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The TMEM16 family of membrane proteins is composed of both Ca-gated Cl channels and Ca-dependent phospholipid scramblases. The functional diversity of TMEM16s underlies their involvement in numerous signal transduction pathways that connect changes in cytosolic Ca levels to cellular signaling networks. Indeed, defects in the function of several TMEM16s cause a variety of genetic disorders, highlighting their fundamental pathophysiological importance. Here, we review how our mechanistic understanding of TMEM16 function has been shaped by recent functional and structural work. Remarkably, the recent determination of near-atomic-resolution structures of TMEM16 proteins of both functional persuasions has revealed how relatively minimal rearrangements in the substrate translocation pathway are sufficient to precipitate the dramatic functional differences that characterize the family. These structures, when interpreted in the light of extensive functional analysis, point to an unusual mechanism for Ca-dependent activation of TMEM16 proteins in which substrate permeation is regulated by a combination of conformational rearrangements and electrostatics. These breakthroughs pave the way to elucidate the mechanistic bases of ion and lipid transport by the TMEM16 proteins and unravel the molecular links between these transport activities and their function in human pathophysiology.

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Section: Introductionmentioning

confidence: 99%

Known structures and unknown mechanisms of TMEM16 scramblases and channels

Falzone

Malvezzi

Lee

et al. 2018

Journal of General Physiology

102

109

View full text Add to dashboard Cite

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Phosphatidylserine-Targeting Monoclonal Antibodies Exhibit Distinct Biochemical and Cellular Effects on Anti-CD3/CD28–Stimulated T Cell IFN-γ and TNF-α Production

Calianese

Kreiss

Kasikara

et al. 2021

The Journal of Immunology

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Phosphatidylserine (PS)-targeting monoclonal Abs (mAbs) that directly target PS and target PS via β2-gp1 (β2GP1) have been in preclinical and clinical development for over 10 y for the treatment of infectious diseases and cancer. Although the intended targets of PS-binding mAbs have traditionally included pathogens as well as stressed tumor cells and its associated vasculature in oncology, the effects of PS-targeting mAbs on activated immune cells, notably T cells, which externalize PS upon Ag stimulation, is not well understood. Using human T cells from healthy donor PBMCs activated with an anti-CD3 + anti-CD28 Ab mixture (anti-CD3/CD28) as a model for TCR-mediated PS externalization and T cell stimulation, we investigated effects of two different PS-targeting mAbs, 11.31 and bavituximab (Bavi), on TCR activation and TCR-mediated cytokine production in an ex vivo paradigm. Although 11.31 and Bavi bind selectivity to anti-CD3/28 activated T cells in a PS-dependent manner, surprisingly, they display distinct functional activities in their effect on IFN-γ and TNF-ɑ production, whereby 11.31, but not Bavi, suppressed cytokine production. This inhibitory effect on anti-CD3/28 activated T cells was observed on both CD4+ and CD8+ cells and independently of monocytes, suggesting the effects of 11.31 were directly mediated by binding to externalized PS on activated T cells. Imaging showed 11.31 and Bavi bind at distinct focal depots on the cell membrane. Collectively, our findings indicate that PS-targeting mAb 11.31 suppresses cytokine production by anti-CD3/28 activated T cells.

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Phospholipid Scramblase: When Phospholipid Asymmetry Goes Away

Cited by 2 publications

References 149 publications

Known structures and unknown mechanisms of TMEM16 scramblases and channels

Known structures and unknown mechanisms of TMEM16 scramblases and channels

Phosphatidylserine-Targeting Monoclonal Antibodies Exhibit Distinct Biochemical and Cellular Effects on Anti-CD3/CD28–Stimulated T Cell IFN-γ and TNF-α Production

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