9kh5

From Proteopedia

(Difference between revisions)

Current revision

Structure of y+LAT1

Structural highlights

9kh5 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 3.74Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

YLAT1_HUMAN Lysinuric protein intolerance. The disease is caused by variants affecting the gene represented in this entry.

Function

YLAT1_HUMAN Heterodimer with SLC3A2, that functions as an antiporter which operates as an efflux route by exporting cationic amino acids from inside the cells in exchange with neutral amino acids plus sodium ions and may participate in nitric oxide synthesis via the transport of L-arginine (PubMed:10080182, PubMed:10655553, PubMed:14603368, PubMed:15756301, PubMed:15776427, PubMed:17329401, PubMed:9829974, PubMed:9878049). Also mediates arginine transport in non-polarized cells, such as monocytes, and is essential for the correct function of these cells (PubMed:15280038, PubMed:31705628). The transport mechanism is electroneutral and operates with a stoichiometry of 1:1 (By similarity). In vitro, Na(+) and Li(+), but also H(+), are cotransported with the neutral amino acids (By similarity).[UniProtKB:Q9R0S5]^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10]

Publication Abstract from PubMed

Heteromeric amino acid transporters (HATs), including y(+)LAT1-4F2hc complex, are responsible for transporting amino acids across membranes, and mutations in y(+)LAT1 cause lysinuric protein intolerance (LPI), a hereditary disorder characterized by defective cationic amino acid transport. The relationship between LPI and specific mutations in y(+)LAT1 has yet to be fully understood. In this study, we characterized the function of y(+)LAT1-4F2hc complex in mammalian cells and determined the cryo-EM structures of the human y(+)LAT1-4F2hc complex in two distinct conformations: the apo state in an inward-open conformation and the native substrate-bound state in an outward-open conformation. Structural analysis suggests that Asp(243) in y(+)LAT1 plays a crucial role in coordination with sodium ion and substrate selectivity. Molecular dynamic (MD) simulations further revealed the different transport mechanism of cationic amino acids and neutral amino acids. These results provide important insights into the mechanisms of the substrate binding and working cycle of HATs.

Structural basis for the substrate recognition and transport mechanism of the human y(+)LAT1-4F2hc transporter complex.,Dai L, Zeng Q, Zhang T, Zhang Y, Shi Y, Li Y, Xu K, Huang J, Wang Z, Zhou Q, Yan R Sci Adv. 2025 Mar 21;11(12):eadq0558. doi: 10.1126/sciadv.adq0558. Epub 2025 Mar , 19. PMID:40106545^[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Torrents D, Mykkänen J, Pineda M, Feliubadaló L, Estévez R, de Cid R, Sanjurjo P, Zorzano A, Nunes V, Huoponen K, Reinikainen A, Simell O, Savontaus ML, Aula P, Palacín M. Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene. Nat Genet. 1999 Mar;21(3):293-6. PMID:10080182 doi:10.1038/6809
↑ Mykkänen J, Torrents D, Pineda M, Camps M, Yoldi ME, Horelli-Kuitunen N, Huoponen K, Heinonen M, Oksanen J, Simell O, Savontaus ML, Zorzano A, Palacín M, Aula P. Functional analysis of novel mutations in y(+)LAT-1 amino acid transporter gene causing lysinuric protein intolerance (LPI). Hum Mol Genet. 2000 Feb 12;9(3):431-8. PMID:10655553 doi:10.1093/hmg/9.3.431
↑ Arancibia-Garavilla Y, Toledo F, Casanello P, Sobrevia L. Nitric oxide synthesis requires activity of the cationic and neutral amino acid transport system y+L in human umbilical vein endothelium. Exp Physiol. 2003 Nov;88(6):699-710. PMID:14603368
↑ Rotoli BM, Bussolati O, Sala R, Barilli A, Talarico E, Gazzola GC, Dall'Asta V. INFgamma stimulates arginine transport through system y+L in human monocytes. FEBS Lett. 2004 Jul 30;571(1-3):177-81. PMID:15280038 doi:10.1016/j.febslet.2004.06.086
↑ Sperandeo MP, Paladino S, Maiuri L, Maroupulos GD, Zurzolo C, Taglialatela M, Andria G, Sebastio G. A y(+)LAT-1 mutant protein interferes with y(+)LAT-2 activity: implications for the molecular pathogenesis of lysinuric protein intolerance. Eur J Hum Genet. 2005 May;13(5):628-34. PMID:15756301 doi:10.1038/sj.ejhg.5201376
↑ Sperandeo MP, Annunziata P, Ammendola V, Fiorito V, Pepe A, Soldovieri MV, Taglialatela M, Andria G, Sebastio G. Lysinuric protein intolerance: identification and functional analysis of mutations of the SLC7A7 gene. Hum Mutat. 2005 Apr;25(4):410. PMID:15776427 doi:10.1002/humu.9323
↑ Rotmann A, Simon A, Martiné U, Habermeier A, Closs EI. Activation of classical protein kinase C decreases transport via systems y+ and y+L. Am J Physiol Cell Physiol. 2007 Jun;292(6):C2259-68. PMID:17329401 doi:10.1152/ajpcell.00323.2006
↑ Rotoli BM, Barilli A, Visigalli R, Ferrari F, Dall'Asta V. y+LAT1 and y+LAT2 contribution to arginine uptake in different human cell models: Implications in the pathophysiology of Lysinuric Protein Intolerance. J Cell Mol Med. 2020 Jan;24(1):921-929. PMID:31705628 doi:10.1111/jcmm.14801
↑ Torrents D, Estevez R, Pineda M, Fernandez E, Lloberas J, Shi YB, Zorzano A, Palacin M. Identification and characterization of a membrane protein (y+L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y+L. A candidate gene for lysinuric protein intolerance. J Biol Chem. 1998 Dec 4;273(49):32437-45. PMID:9829974
↑ Pfeiffer R, Rossier G, Spindler B, Meier C, Kuhn L, Verrey F. Amino acid transport of y+L-type by heterodimers of 4F2hc/CD98 and members of the glycoprotein-associated amino acid transporter family. EMBO J. 1999 Jan 4;18(1):49-57. PMID:9878049 doi:http://dx.doi.org/10.1093/emboj/18.1.49
↑ Dai L, Zeng Q, Zhang T, Zhang Y, Shi Y, Li Y, Xu K, Huang J, Wang Z, Zhou Q, Yan R. Structural basis for the substrate recognition and transport mechanism of the human y(+)LAT1-4F2hc transporter complex. Sci Adv. 2025 Mar 21;11(12):eadq0558. PMID:40106545 doi:10.1126/sciadv.adq0558

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9kh5"

Categories: Homo sapiens | Large Structures | Dai L | Yan RH | Zhang T

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9kh5 is ON HOLD  until 2026-11-09
+==Structure of y+LAT1==
+<StructureSection load='9kh5' size='340' side='right'caption='[[9kh5]], [[Resolution|resolution]] 3.74&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9kh5]] 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=9KH5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9KH5 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]] 3.74&#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=9kh5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9kh5 OCA], [https://pdbe.org/9kh5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9kh5 RCSB], [https://www.ebi.ac.uk/pdbsum/9kh5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9kh5 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/YLAT1_HUMAN YLAT1_HUMAN] Lysinuric protein intolerance. The disease is caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/YLAT1_HUMAN YLAT1_HUMAN] Heterodimer with SLC3A2, that functions as an antiporter which operates as an efflux route by exporting cationic amino acids from inside the cells in exchange with neutral amino acids plus sodium ions and may participate in nitric oxide synthesis via the transport of L-arginine (PubMed:10080182, PubMed:10655553, PubMed:14603368, PubMed:15756301, PubMed:15776427, PubMed:17329401, PubMed:9829974, PubMed:9878049). Also mediates arginine transport in non-polarized cells, such as monocytes, and is essential for the correct function of these cells (PubMed:15280038, PubMed:31705628). The transport mechanism is electroneutral and operates with a stoichiometry of 1:1 (By similarity). In vitro, Na(+) and Li(+), but also H(+), are cotransported with the neutral amino acids (By similarity).[UniProtKB:Q9R0S5]<ref>PMID:10080182</ref> <ref>PMID:10655553</ref> <ref>PMID:14603368</ref> <ref>PMID:15280038</ref> <ref>PMID:15756301</ref> <ref>PMID:15776427</ref> <ref>PMID:17329401</ref> <ref>PMID:31705628</ref> <ref>PMID:9829974</ref> <ref>PMID:9878049</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Heteromeric amino acid transporters (HATs), including y(+)LAT1-4F2hc complex, are responsible for transporting amino acids across membranes, and mutations in y(+)LAT1 cause lysinuric protein intolerance (LPI), a hereditary disorder characterized by defective cationic amino acid transport. The relationship between LPI and specific mutations in y(+)LAT1 has yet to be fully understood. In this study, we characterized the function of y(+)LAT1-4F2hc complex in mammalian cells and determined the cryo-EM structures of the human y(+)LAT1-4F2hc complex in two distinct conformations: the apo state in an inward-open conformation and the native substrate-bound state in an outward-open conformation. Structural analysis suggests that Asp(243) in y(+)LAT1 plays a crucial role in coordination with sodium ion and substrate selectivity. Molecular dynamic (MD) simulations further revealed the different transport mechanism of cationic amino acids and neutral amino acids. These results provide important insights into the mechanisms of the substrate binding and working cycle of HATs.
-Authors:
+Structural basis for the substrate recognition and transport mechanism of the human y(+)LAT1-4F2hc transporter complex.,Dai L, Zeng Q, Zhang T, Zhang Y, Shi Y, Li Y, Xu K, Huang J, Wang Z, Zhou Q, Yan R Sci Adv. 2025 Mar 21;11(12):eadq0558. doi: 10.1126/sciadv.adq0558. Epub 2025 Mar , 19. PMID:40106545<ref>PMID:40106545</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 9kh5" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Dai L]]
+[[Category: Yan RH]]
+[[Category: Zhang T]]

9kh5

From Proteopedia

Current revision

Structure of y+LAT1

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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