Cryo-EM structures of the human surfactant lipid transporter ABCA3

Xie, Tian; Zhang, Zi-Ke; Yue, Jian; Fang, Qi; Gong, Xin

doi:10.1126/sciadv.abn3727

Cited by 12 publications

(5 citation statements)

References 68 publications

(134 reference statements)

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“…Homology modeling was performed with the YASARA Structure program (Krieger et al, 2002). Twenty‐one models of HvABCA2 were built from the atomic coordinates of human phospholipid‐transporting ATPase ABCA3 (PDB code 7W01 and 7W02) (Xie et al, 2022), human phospholipid‐transporting ATPase ABCA1 (PDB code 7TBW and 7TC0) (Sun & Li, 2022) and human retinal‐specific phospholipid‐transporting ATPase ABCA4 (PDB code 7LKZ) (Liu et al, 2021), used as templates. A hybrid model of HvABCA2 was built from the different previous models.…”

Section: Methodsmentioning

confidence: 99%

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Heliothis virescens chymotrypsin is translationally controlled by AeaTMOF binding ABC putative receptor

Borovsky

Rougé

2023

Arch Insect Biochem Physiol

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Heliothis virescens larval chymotrypsin (GenBank accession number AF43709) was cloned, sequenced and its three dimensional (3D) conformation modeled. The enzyme's transcript was first detected 6 days after larval emergence and the transcript level was shown to fall between larval ecdysis periods. Comparisons between the activities of larval gut chymotrypsin and trypsin shows that chymotrypsin activity is only 16% of the total trypsin activity and the pH optimum of the larval chymotrypsin is between pH 9−10, however the enzyme also exhibited a broad activity between pH 4−6. Injections of AeaTMOF and several shorter analogues into 3rd instar larvae followed by Northern blot analyses showed that although the chymotrypsins activities were inhibited by 60%−80% the transcript level of the sequenced chymotrypsin was not reduced and was similar to controls in which the chymotrypsin activity was not inhibited, indicating that AeaTMOF and its analogues exert a translational control. Based on these observations a putative AeaTMOF receptor (ABCC4) homologous to the Ae. aegypti ABC receptor sequence was found in the H. virescens genome. 3D molecular modeling and docking of the AeaTMOF and several of its analogues to the ABCC4 receptor showed that it can bind AeaTMOF and its analogues as was shown before for the Ae. aegypti receptor.

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Section: Methodsmentioning

confidence: 99%

“…Homology modeling was performed with the YASARA Structure program (Krieger et al, 2002). Twenty-one models of HvABCA2 were built from the atomic coordinates of human phospholipid-transporting ATPase ABCA3 (PDB code 7W01 and 7W02) (Xie et al, 2022), human phospholipid-transporting ATPase ABCA1…”

Section: Molecular Modeling Of Hvabca2mentioning

confidence: 99%

Heliothis virescens chymotrypsin is translationally controlled by AeaTMOF binding ABC putative receptor

Borovsky

Rougé

2023

Arch Insect Biochem Physiol

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“…34 The ABCA3 gene encodes a 1704-amino acids protein consisting of two homologous sequences comprising 12 transmembrane helices, the signature ATP-binding cassette motif, two nucleotide binding domains, two regulatory domains and two extracellular domains. 35,36 ABCA3 is involved in the formation of lamellar bodies and is located at their outer membrane where it drives the transportation of phospholipids. 37 Variants in SFTPC induce different cellular effects depending on the localization of the mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the BRICHOS domain of other proteins have been linked to various diseases including dementia, chondrosarcoma and stomach cancer 34 . The ABCA3 gene encodes a 1704‐amino acids protein consisting of two homologous sequences comprising 12 transmembrane helices, the signature ATP‐binding cassette motif, two nucleotide binding domains, two regulatory domains and two extracellular domains 35,36 . ABCA3 is involved in the formation of lamellar bodies and is located at their outer membrane where it drives the transportation of phospholipids 37 …”

Section: Discussionmentioning

confidence: 99%

Similarities and differences of interstitial lung disease associated with pathogenic variants in SFTPC and ABCA3 in adults

Diesler,

Legendre,

Si‐Mohamed

et al. 2024

Respirology

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Background and ObjectiveVariants in surfactant genes SFTPC or ABCA3 are responsible for interstitial lung disease (ILD) in children and adults, with few studies in adults.MethodsWe conducted a multicentre retrospective study of all consecutive adult patients diagnosed with ILD associated with variants in SFTPC or ABCA3 in the French rare pulmonary diseases network, OrphaLung. Variants and chest computed tomography (CT) features were centrally reviewed.ResultsWe included 36 patients (median age: 34 years, 20 males), 22 in the SFTPC group and 14 in the ABCA3 group. Clinical characteristics were similar between groups. Baseline median FVC was 59% ([52–72]) and DLco was 44% ([35–50]). An unclassifiable pattern of fibrosing ILD was the most frequent on chest CT, found in 85% of patients, however with a distinct phenotype with ground‐glass opacities and/or cysts. Nonspecific interstitial pneumonia and usual interstitial pneumonia were the most common histological patterns in the ABCA3 group and in the SFTPC group, respectively. Annually, FVC and DLCO declined by 1.87% and 2.43% in the SFTPC group, respectively, and by 0.72% and 0.95% in the ABCA3 group, respectively (FVC, p = 0.014 and DLCO, p = 0.004 for comparison between groups). Median time to death or lung transplantation was 10 years in the SFTPC group and was not reached at the end of follow‐up in the ABCA3 group.ConclusionSFTPC and ABCA3‐associated ILD present with a distinct phenotype and prognosis. A radiologic pattern of fibrosing ILD with ground‐glass opacities and/or cysts is frequently found in these rare conditions.

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“…Following synthesis, pulmonary surfactant lipids are stored in MLBs before secretion. The transport of surfactant lipids, such as PC, phosphatidylglycerol and cholesterol, within these organelles is mediated by the ABCA3 transporter, which is localized in the limiting membranes of MLBs [147]. The importance of this transporter in surfactant homeostasis is demonstrated by the fact that mutations in the ABCA3 gene can cause surfactant-deficient pulmonary disorders, such as fatal neonatal surfactant deficiency, chronic interstitial lung disease and diffuse parenchymal lung disease [148].…”

Section: Molecular Mechanisms Leading To Cigarette-smoke-induced Modi...mentioning

confidence: 99%

Molecular Impact of Conventional and Electronic Cigarettes on Pulmonary Surfactant

Garavaglia

Bodega

Porta

et al. 2023

IJMS

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The alveolar epithelium is covered by a non-cellular layer consisting of an aqueous hypophase topped by pulmonary surfactant, a lipo-protein mixture with surface-active properties. Exposure to cigarette smoke (CS) affects lung physiology and is linked to the development of several diseases. The macroscopic effects of CS are determined by several types of cell and molecular dysfunction, which, among other consequences, lead to surfactant alterations. The purpose of this review is to summarize the published studies aimed at uncovering the effects of CS on both the lipid and protein constituents of surfactant, discussing the molecular mechanisms involved in surfactant homeostasis that are altered by CS. Although surfactant homeostasis has been the topic of several studies and some molecular pathways can be deduced from an analysis of the literature, it remains evident that many aspects of the mechanisms of action of CS on surfactant homeostasis deserve further investigation.

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Cryo-EM structures of the human surfactant lipid transporter ABCA3

Cited by 12 publications

References 68 publications

Heliothis virescens chymotrypsin is translationally controlled by AeaTMOF binding ABC putative receptor

Heliothis virescens chymotrypsin is translationally controlled by AeaTMOF binding ABC putative receptor

Similarities and differences of interstitial lung disease associated with pathogenic variants in SFTPC and ABCA3 in adults

Molecular Impact of Conventional and Electronic Cigarettes on Pulmonary Surfactant

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