phospholipid flippase
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2021 ◽  
Author(s):  
Tao Li ◽  
Diankun Yu ◽  
Hayeon C Oak ◽  
Beika Zhu ◽  
Li Wang ◽  
...  


2021 ◽  
Author(s):  
Justin Pater ◽  
Cindy Penney ◽  
Darren O’Rielly ◽  
Anne Griffin ◽  
Mordechai Shohat ◽  
...  

Abstract Whole genome approaches are superior for identifying recessive genes, however discovery of dominant genes including deafness genes (DFNA) remains challenging. Herein we report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Targeted screening of DFNA genes based on audioprofiles was unsuccessful. Genome-wide SNP genotyping linked SNHL to DFNA33 (Lod = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL in 2009. WGS identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 Kb, excluding all but one variant. ATP11A (NC_000013.11: g.190616G > A) is a novel point mutation predicted to be a cryptic donor splice site. RNA studies in patient-derived tissues verified in silico predictions, revealing the retention of 153bp of intron in the 3’ UTR of several ATP11A isoforms. A second, unresolved family from Israel with a similar, variable form of SNHL and a novel duplication in exon 28 of ATP11A that occurs within the splice donor sequence (intron 28). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.



2021 ◽  
Author(s):  
Zhenke Yang ◽  
Yang Shi ◽  
Huiting Cui ◽  
Shuzhen Yang ◽  
Han Gao ◽  
...  

Mosquito midgut epithelium traversal is an essential component of transmission of malaria parasites. Phospholipid flippases are eukaryotic type IV ATPases (P4-ATPases), which in association with CDC50 cofactors, translocate phospholipids across lipid bilayers to maintain the membrane asymmetry. In this study, we investigated the function of a putative P4-ATPase, ATP7, from the rodent malaria parasite P. yoelii. Disruption of ATP7 results in block of parasite infection of mosquitoes. ATP7 is localized on the ookinete plasma membrane. While ATP7-depleted ookinetes are motile and capable of invading the midgut, they are quickly eliminated within the epithelial cells by a process that is independent from the mosquito complement-like immunity. ATP7 colocalizes and interacts with the flippase co-factor CDC50C. Importantly, depletion of CDC50C phenocopies ATP7 deficiency. ATP7-depleted ookinetes fail to translocate phosphatidylcholine (PC) across the plasma membrane, resulting in PC exposure at the ookinete surface. Lastly, ookinete microinjection into the mosquito hemocoel reverses the ATP7 deficiency phenotype. Our study identifies Plasmodium flippase as a novel mechanism of parasite survival in the midgut epithelium that is required for mosquito transmission.



2020 ◽  
Vol 11 ◽  
Author(s):  
Juliette Salvaing ◽  
César Botella ◽  
Catherine Albrieux ◽  
Valérie Gros ◽  
Maryse A. Block ◽  
...  


2020 ◽  
Vol 295 (30) ◽  
pp. 10180-10194 ◽  
Author(s):  
Hanayo Nakanishi ◽  
Katsumasa Irie ◽  
Katsumori Segawa ◽  
Kazuya Hasegawa ◽  
Yoshinori Fujiyoshi ◽  
...  

ATP11C, a member of the P4-ATPase flippase, translocates phosphatidylserine from the outer to the inner plasma membrane leaflet, and maintains the asymmetric distribution of phosphatidylserine in the living cell. We present the crystal structures of a human plasma membrane flippase, ATP11C–CDC50A complex, in a stabilized E2P conformation. The structure revealed a deep longitudinal crevice along transmembrane helices continuing from the cell surface to the phospholipid occlusion site in the middle of the membrane. We observed that the extension of the crevice on the exoplasmic side is open, and the complex is therefore in an outward-open E2P state, similar to a recently reported cryo-EM structure of yeast flippase Drs2p–Cdc50p complex. We noted extra densities, most likely bound phosphatidylserines, in the crevice and in its extension to the extracellular side. One was close to the phosphatidylserine occlusion site as previously reported for the human ATP8A1–CDC50A complex, and the other in a cavity at the surface of the exoplasmic leaflet of the bilayer. Substitutions in either of the binding sites or along the path between them impaired specific ATPase and transport activities. These results provide evidence that the observed crevice is the conduit along that phosphatidylserine traverses from the outer leaflet to its occlusion site in the membrane and suggest that the exoplasmic cavity is important for phospholipid recognition. They also yield insights into how phosphatidylserine is incorporated from the outer leaflet of the plasma membrane into the transmembrane.



2020 ◽  
Vol 60 (4) ◽  
pp. 222-226
Author(s):  
Yuji HARA ◽  
Masaki TSUCHIYA ◽  
Kotaro HIRANO ◽  
Masato UMEDA


Author(s):  
Hanayo Nakanishi ◽  
Katsumasa Irie ◽  
Katsumori Segawa ◽  
Kazuya Hasegawa ◽  
Yoshinori Fujiyoshi ◽  
...  

AbstractATP11C, a member of P4-ATPase flippase, exclusively translocates phosphatidylserine from the outer to the inner leaflets of the plasma membrane, and maintains the asymmetric distribution of phosphatidylserine in the living cell. However, the mechanisms by which ATP11C translocates phosphatidylserine remain elusive. Here we show the crystal structures of a human plasma membrane flippase, ATP11C-CDC50A complex, in an outward-open E2P conformation. Two phosphatidylserine molecules are in a conduit that continues from the cell surface to the occlusion site in the middle of the membrane. Mutations in either of the phosphotidylserine binding sites or along the pathway between significantly impairs specific ATPase and transport activities. We propose a model for phosphatidylserine translocation from the outer to the inner leaflet of the plasma membrane.



2019 ◽  
Vol 294 (17) ◽  
pp. 6809-6821 ◽  
Author(s):  
Angela Y. Liou ◽  
Laurie L. Molday ◽  
Jiao Wang ◽  
Jens Peter Andersen ◽  
Robert S. Molday


2019 ◽  
Vol 294 (15) ◽  
pp. 5970-5979 ◽  
Author(s):  
Stine A. Mikkelsen ◽  
Louise S. Mogensen ◽  
Bente Vilsen ◽  
Robert S. Molday ◽  
Anna L. Vestergaard ◽  
...  


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