View source for 8qcs


==Cryo-EM structure of the inward-facing FLVCR1==
<StructureSection load='8qcs' size='340' side='right'caption='[[8qcs]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8qcs]] 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=8QCS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8QCS 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]] 2.9&#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=8qcs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8qcs OCA], [https://pdbe.org/8qcs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8qcs RCSB], [https://www.ebi.ac.uk/pdbsum/8qcs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8qcs ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/FLVC1_HUMAN FLVC1_HUMAN] Posterior column ataxia-retinitis pigmentosa syndrome. The disease is caused by variants affecting the gene represented in this entry. Defective neuronal heme transmembrane export due to FLVCR1 mutations may abrogate the neuroprotective effects of neuroglobin and initiate an apoptotic cascade that results in the selective degeneration of photoreceptors in the neurosensory retina and sensory neurons in the posterior spinal cord.  Defects in FLVCR1 are a cause of a sensory neuropathy resulting in pain insensitivity. Patients have decreased sensing of pain, temperature and touch. Self-injury, ulcers and amputations are commonly observed in affected individuals.<ref>PMID:27923065</ref> 
== Function ==
[https://www.uniprot.org/uniprot/FLVC1_HUMAN FLVC1_HUMAN] Heme b transporter that mediates heme efflux from the cytoplasm to the extracellular compartment. Heme export depends on the presence of HPX and is required to maintain intracellular free heme balance, protecting cells from heme toxicity. Heme export provides protection from heme or ferrous iron toxicities in liver, brain, sensory neurons and during erythropoiesis, a process in which heme synthesis intensifies. Possibly export coproporphyrin and protoporphyrin IX, which are both intermediate products in the heme biosynthetic pathway. Does not export bilirubin. The molecular mechanism of heme transport, whether electrogenic, electroneutral or coupled to other ions, remains to be elucidated.<ref>PMID:15369674</ref> <ref>PMID:20610401</ref> <ref>PMID:23187127</ref> <ref>PMID:27923065</ref>   (Microbial infection) Confers susceptibility to feline leukemia virus subgroup C (FeLV-C) infection in vitro.<ref>PMID:10400745</ref>   Heme b transporter that promotes heme efflux from the mitochondrion to the cytoplasm. Essential for erythroid differentiation.<ref>PMID:23187127</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily(1). Their dysfunction is linked to several clinical disorders, including PCARP, HSAN and Fowler syndrome(2-7). Earlier studies concluded that FLVCR1 may function as a haem exporter(8-12), whereas FLVCR2 was suggested to act as a haem importer(13), yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters(14-16). Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across the plasma membrane, using a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unravelled the coordination chemistry underlying their substrate interactions. Fully conserved tryptophan and tyrosine residues form the binding pocket of both transporters and confer selectivity for choline and ethanolamine through cation-pi interactions. Our findings clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhance our comprehension of disease-associated mutations that interfere with these vital processes and shed light on the conformational dynamics of these major facilitator superfamily proteins during the transport cycle.

Molecular mechanism of choline and ethanolamine transport in humans.,Ri K, Weng TH, Claveras Cabezudo A, Josting W, Zhang Y, Bazzone A, Leong NCP, Welsch S, Doty RT, Gursu G, Lim TJY, Schmidt SL, Abkowitz JL, Hummer G, Wu D, Nguyen LN, Safarian S Nature. 2024 May 22. doi: 10.1038/s41586-024-07444-7. PMID:38778100<ref>PMID:38778100</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8qcs" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Safarian S]]
[[Category: Weng T-H]]
[[Category: Wu D]]