View source for 8iel


==Cryo-EM structure of ATP13A2 in the E1-like state==
<StructureSection load='8iel' size='340' side='right'caption='[[8iel]], [[Resolution|resolution]] 5.65&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8iel]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8IEL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8IEL FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 5.65&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8iel FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8iel OCA], [https://pdbe.org/8iel PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8iel RCSB], [https://www.ebi.ac.uk/pdbsum/8iel PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8iel ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/AT132_HUMAN AT132_HUMAN] Autosomal recessive spastic paraplegia type 78;Kufor-Rakeb syndrome;ATP13A2-related juvenile neuronal ceroid lipofuscinosis. The disease is caused by variants affecting the gene represented in this entry. KRS has also been referred to as neuronal ceroid lipofuscinosis 12 (CLN12), due to neuronal and glial lipofuscin deposits detected in the cortex, basal nuclei and cerebellum of some patients.<ref>PMID:22388936</ref>   The disease is caused by variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/AT132_HUMAN AT132_HUMAN] ATPase which acts as a lysosomal polyamine exporter with high affinity for spermine (PubMed:31996848). Also stimulates cellular uptake of polyamines and protects against polyamine toxicity (PubMed:31996848). Plays a role in intracellular cation homeostasis and the maintenance of neuronal integrity (PubMed:22186024). Contributes to cellular zinc homeostasis (PubMed:24603074). Confers cellular protection against Mn(2+) and Zn(2+) toxicity and mitochondrial stress (PubMed:26134396). Required for proper lysosomal and mitochondrial maintenance (PubMed:22296644, PubMed:28137957). Regulates the autophagy-lysosome pathway through the control of SYT11 expression at both transcriptional and post-translational levels (PubMed:27278822). Facilitates recruitment of deacetylase HDAC6 to lysosomes to deacetylate CTTN, leading to actin polymerization, promotion of autophagosome-lysosome fusion and completion of autophagy (PubMed:30538141). Promotes secretion of exosomes as well as secretion of SCNA via exosomes (PubMed:25392495, PubMed:24603074). Plays a role in lipid homeostasis (PubMed:31132336).<ref>PMID:22186024</ref> <ref>PMID:22296644</ref> <ref>PMID:24603074</ref> <ref>PMID:25392495</ref> <ref>PMID:26134396</ref> <ref>PMID:27278822</ref> <ref>PMID:28137957</ref> <ref>PMID:30538141</ref> <ref>PMID:31132336</ref> <ref>PMID:31996848</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Dysregulation of polyamine homeostasis strongly associates with human diseases. ATP13A2, which is mutated in juvenile-onset Parkinson's disease and autosomal recessive spastic paraplegia 78, is a transporter with a critical role in balancing the polyamine concentration between the lysosome and the cytosol. Here, to better understand human ATP13A2-mediated polyamine transport, we use single-particle cryo-electron microscopy to solve high-resolution structures of human ATP13A2 in six intermediate states, including the putative E2 structure for the P5 subfamily of the P-type ATPases. These structures comprise a nearly complete conformational cycle spanning the polyamine transport process and capture multiple substrate binding sites distributed along the transmembrane regions, suggesting a potential polyamine transport pathway. Integration of high-resolution structures, biochemical assays, and molecular dynamics simulations allows us to obtain a better understanding of the structural basis of how hATP13A2 transports polyamines, providing a mechanistic framework for ATP13A2-related diseases.

Conformational cycle of human polyamine transporter ATP13A2.,Mu J, Xue C, Fu L, Yu Z, Nie M, Wu M, Chen X, Liu K, Bu R, Huang Y, Yang B, Han J, Jiang Q, Chan KC, Zhou R, Li H, Huang A, Wang Y, Liu Z Nat Commun. 2023 Apr 8;14(1):1978. doi: 10.1038/s41467-023-37741-0. PMID:37031211<ref>PMID:37031211</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8iel" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Liu ZM]]
[[Category: Mu JQ]]
[[Category: Xue CY]]