Bioinformatic characterization of the Anoctamin Superfamily of Ca2+-activated ion channels and lipid scramblases

Medrano-Soto, Arturo; Moreno–Hagelsieb, Gabriel; McLaughlin, Daniel F.; Ye, Zachary S.; Hendargo, Kevin J.; Saier, Milton H.

doi:10.1371/journal.pone.0192851

Cited by 58 publications

(78 citation statements)

References 116 publications

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“…This classification indicates that OsOSCA1.2 is distantly related to members of the Anoctamin family (ANO; TC: 1.A.17.1) for which high-resolution 3D structure are available (10, 11). Following a recently published bioinformatics approach (5), we had further predicted that OsOSCA1.2 had eleven TMs and the eighth hydrophobicity peak is composed of two TMs ( Fig. 1B ) based on hydropathy analysis and comparison of regions with the fungal homolog Nectria haematococca TMEM16 (NhTMEM16) (10).…”

Section: Resultsmentioning

confidence: 99%

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Cryo-EM Structure of OSCA1.2 from Oryza sativa: Mechanical basis of hyperosmolality-gating in Plants

Maity

Heumann

McGrath

et al. 2018

Preprint

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1Cryo-EM structure of OSCA1.2 from Oryza sativa: Mechanical basis of 2 hyperosmolality-gating in plants 3 4 5Abstract 46Sensing and responding to environmental water deficiency and osmotic stresses is 47 essential for the growth, development and survival of plants. Recently, sensing ion channel called OSCA1 was discovered that functions in sensing 49 hyperosmolality in Arabidopsis. Here, we report the cryo-EM structure and function of 50 an ion channel from rice (Oryza sativa; OsOSCA1.2), showing how it mediates 51 hyperosmolality sensing and ion permeability. The structure reveals a dimer; the 52 molecular architecture of each subunit consists of eleven transmembrane helices and 53 a cytosolic soluble domain that has homology to RNA recognition proteins. The 54transmembrane domain is structurally related to the TMEM16 family of calcium 55 dependent ion channels and scramblases. The cytosolic soluble domain possesses a 56 distinct structural feature in the form of extended intracellular helical arms that is 57parallel to the plasma membrane. These helical arms are well positioned to sense 58 lateral tension on the inner leaflet of the lipid bilayer caused by changes in turgor 59pressure. Computational dynamic analysis suggests how this domain couples to the 60 transmembrane portion of the molecule to open the channel. Hydrogen-deuterium 61 exchange mass spectrometry (HDXMS) experimentally confirms the conformational 62 dynamics of these coupled domains. The structure provides a framework to 63understand the structural basis of hyperosmolality sensing in an important crop plant, 64 extends our knowledge of the anoctamin superfamily important for plants and fungi, 65and provides a structural mechanism for translating membrane stress to ion transport 66 regulation. 67 68Introduction 69Hyperosmolarity and osmotic stress are among the first physiological responses to 70 changes in salinity and drought. Hyperosmolality triggers increases in cytosolic free 71Ca 2+ concentration and thereby initiates an osmotic stress-induced signal transduction 72 cascade in plants (1-3). Salinity and drought stress trigger diverse protective 73 mechanisms in plants enabling enhanced drought tolerance and reduction of water 74 loss in leaves. 75 76Ion channels have long been hypothesized as sensors of osmotic stress. A candidate 77 membrane protein named OSCA was isolated in a genetic screen for mutants that 78impair the rapid osmotic stress-induced Ca 2+ elevation in plants (1). OSCA1 encodes 79 a multi-spanning membrane protein that functions in osmotic/mechanical stress-80induced activation of ion currents. However, the underlying mechanisms and whether 81OSCA1 itself encodes an ion conducting pore specific for Ca 2+ requires further 82analysis. OSCA1 is a member of a larger gene family in Arabidopsis with 15 members 83(4), and with many homologs encoded in other plants and fungal genomes. 84Furthermore, evolutionary analyses have revealed that OSCA is distantly related to 85 the anoctamin superfamily, that includes the TMEM16 family...

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Section: Resultsmentioning

confidence: 99%

“…OSCA1 is a member of a larger gene family in Arabidopsis with 15 members (4), and with many homologs encoded in other plants and fungal genomes. Furthermore, evolutionary analyses have revealed that OSCA is distantly related to the anoctamin superfamily, that includes the TMEM16 family of calcium dependent ion channels (5).…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM Structure of OSCA1.2 from Oryza sativa: Mechanical basis of hyperosmolality-gating in Plants

Maity

Heumann

McGrath

et al. 2018

Preprint

Self Cite

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“…Our structural study of OSCA1.2 elucidates a novel architecture for MA ion channel and reveals unanticipated similarities between OSCA1.2 and TMEM16 proteins, including pore structure. Intriguingly, transmembrane-channel-like (TMC) proteins, which are candidate pore-forming subunits of the hair cell mechanoelectrical transduction (MET) apparatus 26-28 , are distantly related to the TMEM16 family and proposed to have the same topology 29-31 . Although the molecular identity of the MET ion channel remains controversial 27 , the shared TM topology between more distantly related TMEM16s and OSCA1.2 suggests a similar fold for TMCs.…”

Section: Mainmentioning

confidence: 99%

Cryo-EM structure of the mechanically activated ion channel OSCA1.2

Jojoa-Cruz

Saotome

Murthy

et al. 2018

Preprint

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Main 41We purified Arabidopsis thaliana OSCA1.2 expressed in HEK293F cells and determined 42 cryo-EM reconstructions in lipidic nanodiscs and LMNG detergent micelle with cholesteryl 43 hemisuccinate (CHS) ( Fig. 1a-d, Extended Data Figs. 1,2). The resulting density maps 44 allowed building of 82% of the full-length OSCA1.2 sequence (Extended Data Fig. 3, 45 Extended Data Table 1). Structures of OSCA1.2 in nanodisc and LMNG were nearly 46 identical (RMSD=0.81 Å, Extended Data Fig. 4a-c). We refer to the nanodisc structure 47

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“…The groundbreaking discoveries of TMEM16A 3 and TMEM16B as the long-sought CaCCs (1-3) revealed a novel membrane protein superfamily that includes the TMEM16 family and its closely related OSCA, TMEM63, and TMC membrane protein families (4,5). TMEM16 proteins have been found in fungi (6,7), amoeboids (8), insects (9), and vertebrates (10 -12).…”

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confidence: 99%

Drosophila Subdued is a moonlighting transmembrane protein 16 (TMEM16) that transports ions and phospholipids

Yang

2019

Journal of Biological Chemistry

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Transmembrane protein 16 (TMEM16) family members play numerous important physiological roles, ranging from controlling membrane excitability and secretion to mediating blood coagulation and viral infection. These diverse functions are largely due to their distinct biophysical properties. Mammalian TMEM16A and TMEM16B are Ca 2؉ -activated Cl ؊ channels (CaCCs), whereas mammalian TMEM16F, fungal afTMEM16, and nhTMEM16 are moonlighting (multifunctional) proteins with both Ca 2؉ -activated phospholipid scramblase (CaPLSase) and Ca 2؉ -activated, nonselective ion channel (CAN) activities. To further understand the biological functions of the enigmatic TMEM16 proteins in different organisms, here, by combining an improved annexin V-based CaPLSase-imaging assay with inside-out patch clamp technique, we thoroughly characterized Subdued, a Drosophila TMEM16 ortholog. We show that Subdued is also a moonlighting transport protein with both CAN and CaPLSase activities. Using a TMEM16F-deficient HEK293T cell line to avoid strong interference from endogenous CaPLSases, our functional characterization and mutagenesis studies revealed that Subdued is a bona fide CaPLSase. Our finding that Subdued is a moonlighting TMEM16 expands our understanding of the molecular mechanisms of TMEM16 proteins and their evolution and physiology in both Drosophila and humans.

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Bioinformatic characterization of the Anoctamin Superfamily of Ca2+-activated ion channels and lipid scramblases

Cited by 58 publications

References 116 publications

Cryo-EM Structure of OSCA1.2 from Oryza sativa: Mechanical basis of hyperosmolality-gating in Plants

Cryo-EM Structure of OSCA1.2 from Oryza sativa: Mechanical basis of hyperosmolality-gating in Plants

Cryo-EM structure of the mechanically activated ion channel OSCA1.2

Drosophila Subdued is a moonlighting transmembrane protein 16 (TMEM16) that transports ions and phospholipids

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