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9vdm

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Cryo-EM structure of human ATP9A (AMPPCP) E2P state open form

Structural highlights

9vdm is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.01Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ATP9A_HUMAN Non-specific syndromic intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Function

ATP9A_HUMAN Plays a role in regulating membrane trafficking of cargo proteins, namely endosome to plasma membrane recycling, probably acting through RAB5 and RAB11 activation (PubMed:27733620, PubMed:30213940, PubMed:36604604). Also involved in endosome to trans-Golgi network retrograde transport (PubMed:27733620, PubMed:30213940). In complex with MON2 and DOP1B, regulates SNX3 retromer-mediated endosomal sorting of WLS, a transporter of Wnt morphogens in developing tissues. Participates in the formation of endosomal carriers that direct WLS trafficking back to Golgi, away from lysosomal degradation (PubMed:30213940). Appears to be implicated in intercellular communication by negatively regulating the release of exosomes (PubMed:30947313). The flippase activity towards membrane lipids and its role in membrane asymmetry remains to be proved (PubMed:30947313). Required for the maintenance of neurite morphology and synaptic transmission (By similarity).[UniProtKB:O70228]^[1] ^[2] ^[3] ^[4]

References

↑ Tanaka Y, Ono N, Shima T, Tanaka G, Katoh Y, Nakayama K, Takatsu H, Shin HW. The phospholipid flippase ATP9A is required for the recycling pathway from the endosomes to the plasma membrane. Mol Biol Cell. 2016 Dec 1;27(24):3883-3893. PMID:27733620 doi:10.1091/mbc.E16-08-0586
↑ McGough IJ, de Groot REA, Jellett AP, Betist MC, Varandas KC, Danson CM, Heesom KJ, Korswagen HC, Cullen PJ. SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion. Nat Commun. 2018 Sep 13;9(1):3737. PMID:30213940 doi:10.1038/s41467-018-06114-3
↑ Naik J, Hau CM, Ten Bloemendaal L, Mok KS, Hajji N, Wehman AM, Meisner S, Muncan V, Paauw NJ, de Vries HE, Nieuwland R, Paulusma CC, Bosma PJ. The P4-ATPase ATP9A is a novel determinant of exosome release. PLoS One. 2019 Apr 4;14(4):e0213069. PMID:30947313 doi:10.1371/journal.pone.0213069
↑ Meng T, Chen X, He Z, Huang H, Lin S, Liu K, Bai G, Liu H, Xu M, Zhuang H, Zhang Y, Waqas A, Liu Q, Zhang C, Sun XD, Huang H, Umair M, Yan Y, Feng D. ATP9A deficiency causes ADHD and aberrant endosomal recycling via modulating RAB5 and RAB11 activity. Mol Psychiatry. 2023 Mar;28(3):1219-1231. PMID:36604604 doi:10.1038/s41380-022-01940-w