X-Ray Structure of a Calcium Activated TMEM16 Lipid Scramblase

Brunner, Janine D.; Lim, Novandy K.; Schenck, Stephan

doi:10.1016/j.bpj.2014.11.1881

Cited by 89 publications

(212 citation statements)

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“…can coordinate with Ca 2+ . Consistent with previous studies (Brunner et al, 2014;Tien et al, 2014;Yu et al, 2012), Dang et al (2017) found that the acidic residues E654, E702, E705, E734, and D738 group together to form two Ca 2+ -binding sites in TMEM16A. The present data have provided a framework to guide further studies of gating of CaCCs.…”

supporting

confidence: 91%

Recent advances in TMEM16A: Structure, function, and disease

Guo

Wang

et al. 2018

Journal Cellular Physiology

103

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TMEM16A (also known as anoctamin 1, ANO1) is the molecular basis of the calcium‐activated chloride channels, with ten transmembrane segments. Recently, atomic structures of the transmembrane domains of mouse TMEM16A (mTMEM16A) were determined by single‐particle electron cryomicroscopy. This gives us a solid ground to discuss the electrophysiological properties and functions of TMEM16A. TMEM16A is reported to be dually regulated by Ca2+ and voltage. In addition, the dysfunction of TMEM16A has been found to be involved in many diseases including cystic fibrosis, various cancers, hypertension, and gastrointestinal motility disorders. TMEM16A is overexpressed in many cancers, including gastrointestinal stromal tumors, gastric cancer, head and neck squamous cell carcinoma (HNSCC), colon cancer, pancreatic ductal adenocarcinoma, and esophageal cancer. Furthermore, overexpression of TMEM16A is related to the occurrence, proliferation, and migration of tumor cells. To date, several studies have shown that many natural compounds and synthetic compounds have regulatory effects on TMEM16A. These small molecule compounds might be novel drugs for the treatment of diseases caused by TMEM16A dysfunction in the future. In addition, recent studies have shown that TMEM16A plays different roles in different diseases through different signal transduction pathways. This review discusses the topology, electrophysiological properties, modulators and functions of TMEM16A in mediates nociception, gastrointestinal dysfunction, hypertension, and cancer and focuses on multiple regulatory mechanisms regarding TMEM16A.

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supporting

confidence: 91%

Recent advances in TMEM16A: Structure, function, and disease

Guo

Wang

et al. 2018

Journal Cellular Physiology

103

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“…23 Anoctamins can also function as phospholipid scramblases when activated by increases in calcium levels, whereby they promote cell death by moving phosphatidylserine from the inner to the outer leaflet of the plasma membrane. 24 Further, the expression of several members of F I G U R E 1 ANO3 rs74754887, ANO4 rs585335, ANO5 rs4622263, ANO7 rs62187431, and ANO10 rs118005571 are associated with biochemical recurrence (BCR)-free survival time. Values between brackets denote the number of patients F I G U R E 2 Functional analyses of candidate single-nucleotide polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

Genetic association analysis identifies a role for ANO5 in prostate cancer progression

Chen

Huang

et al. 2020

Cancer Medicine

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Anoctamins were originally identified as a family of calcium‐activated chloride channels, but recently their roles in the development of different types of malignancies were suggested. Here, we evaluated the associations between 211 common single‐nucleotide polymorphisms in 10 anoctamin genes with biochemical recurrence (BCR) after radical prostatectomy (RP) for localized prostate cancer. Four SNPs (ANO4 rs585335, ANO5 rs4622263, ANO7 rs62187431, and ANO10 rs118005571) remained significantly associated with BCR after multiple test correction (P < .05 and q = 0.232) and adjustment for known prognostic factors. Expression quantitative trait loci analysis found that ANO5 rs4622263 C and ANO10 rs118005571 C alleles were associated with decreased mRNA expression levels. Moreover, lower expression of ANO5 was correlated with more advanced tumors and poorer outcomes in two independent prostate cancer cohorts. Taken together, ANO5 rs4622263 was associated with BCR, and ANO5 gene expression was correlated with patient prognosis, suggesting a pivotal role for ANO5 in prostate cancer progression.

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“…In a murine B-cell line model, the silencing of Ano6 resulted in an impairment of Ca 2+ -dependent PS exposure (12). A role of Anos as transporters for the negatively charged PS was also confirmed by structural analysis (14). In addition, there is substantial electrophysiological evidence that Ano6, like other members of the Ano family, can operate as aCa 2+ -induced ion channel that is permeable to chloride ions, monovalent cations, and calcium ions (10,(15)(16)(17).…”

mentioning

confidence: 85%

Survival protein anoctamin‐6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage

Mattheij

Braun²,

Kruchten

et al. 2015

FASEB j.

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Scott syndrome is a rare bleeding disorder, characterized by altered Ca(2+)-dependent platelet signaling with defective phosphatidylserine (PS) exposure and microparticle formation, and is linked to mutations in the ANO6 gene, encoding anoctamin (Ano)6. We investigated how the complex platelet phenotype of this syndrome is linked to defective expression of Anos or other ion channels. Mice were generated with heterozygous of homozygous deficiency in Ano6, Ano1, or Ca(2+)-dependent KCa3.1 Gardos channel. Platelets from these mice were extensively analyzed on molecular functions and compared with platelets from a patient with Scott syndrome. Deficiency in Ano1 or Gardos channel did not reduce platelet responses compared with control mice (P > 0.1). In 2 mouse strains, deficiency in Ano6 resulted in reduced viability with increased bleeding time to 28.6 min (control 6.4 min, P < 0.05). Platelets from the surviving Ano6-deficient mice resembled platelets from patients with Scott syndrome in: 1) normal collagen-induced aggregate formation (P > 0.05) with reduced PS exposure (-65 to 90%); 2) lowered Ca(2+)-dependent swelling (-80%) and membrane blebbing (-90%); 3) reduced calpain-dependent protein cleavage (-60%); and 4) moderately affected apoptosis-dependent PS exposure. In conclusion, mouse deficiency of Ano6 but not of other channels affects viability and phenocopies the complex changes in platelets from hemostatically impaired patients with Scott syndrome.

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X-Ray Structure of a Calcium Activated TMEM16 Lipid Scramblase

Cited by 89 publications

References 0 publications

Recent advances in TMEM16A: Structure, function, and disease

Recent advances in TMEM16A: Structure, function, and disease

Genetic association analysis identifies a role for ANO5 in prostate cancer progression

Survival protein anoctamin‐6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage

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