6jmq

From Proteopedia

(Difference between revisions)

Current revision

LAT1-CD98hc complex bound to MEM-108 Fab

6jmq, resolution 3.31Å

Structural highlights

6jmq is a 4 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.31Å
Ligands:
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LAT1_HUMAN Sodium-independent, high-affinity transport of large neutral amino acids such as phenylalanine, tyrosine, leucine, arginine and tryptophan, when associated with SLC3A2/4F2hc. Involved in cellular amino acid uptake. Acts as an amino acid exchanger. Involved in the transport of L-DOPA across the blood-brain barrier, and that of thyroid hormones triiodothyronine (T3) and thyroxine (T4) across the cell membrane in tissues such as placenta. Plays a role in neuronal cell proliferation (neurogenesis) in brain. Involved in the uptake of methylmercury (MeHg) when administered as the L-cysteine or D,L-homocysteine complexes, and hence plays a role in metal ion homeostasis and toxicity. Involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the transmembrane. May play an important role in high-grade gliomas. Mediates blood-to-retina L-leucine transport across the inner blood-retinal barrier which in turn may play a key role in maintaining large neutral amino acids as well as neurotransmitters in the neural retina. Acts as the major transporter of tyrosine in fibroblasts. When associated with LAPTM4B, recruits SLC3A2 and SLC7A5 to lysosomes to promote leucine uptake into these organelles and is required for mTORC1 activation (PubMed:25998567).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14] ^[15]

Publication Abstract from PubMed

The L-type amino acid transporter 1 (LAT1 or SLC7A5) transports large neutral amino acids across the membrane and is crucial for brain drug delivery and tumor growth. LAT1 forms a disulfide-linked heterodimer with CD98 heavy chain (CD98hc, 4F2hc or SLC3A2), but the mechanism of assembly and amino acid transport are poorly understood. Here we report the cryo-EM structure of the human LAT1-CD98hc heterodimer at 3.3-A resolution. LAT1 features a canonical Leu T-fold and exhibits an unusual loop structure on transmembrane helix 6, creating an extended cavity that might accommodate bulky amino acids and drugs. CD98hc engages with LAT1 through the extracellular, transmembrane and putative cholesterol-mediated interactions. We also show that two anti-CD98 antibodies recognize distinct, multiple epitopes on CD98hc but not its glycans, explaining their robust reactivities. These results reveal the principles of glycoprotein-solute carrier assembly and provide templates for improving preclinical drugs and antibodies targeting LAT1 or CD98hc.

Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc.,Lee Y, Wiriyasermkul P, Jin C, Quan L, Ohgaki R, Okuda S, Kusakizako T, Nishizawa T, Oda K, Ishitani R, Yokoyama T, Nakane T, Shirouzu M, Endou H, Nagamori S, Kanai Y, Nureki O Nat Struct Mol Biol. 2019 Jun;26(6):510-517. doi: 10.1038/s41594-019-0237-7. Epub, 2019 Jun 3. PMID:31160781^[16]

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

References

↑ Prasad PD, Wang H, Huang W, Kekuda R, Rajan DP, Leibach FH, Ganapathy V. Human LAT1, a subunit of system L amino acid transporter: molecular cloning and transport function. Biochem Biophys Res Commun. 1999 Feb 16;255(2):283-8. doi:, 10.1006/bbrc.1999.0206. PMID:10049700 doi:http://dx.doi.org/10.1006/bbrc.1999.0206
↑ Pineda M, Fernandez E, Torrents D, Estevez R, Lopez C, Camps M, Lloberas J, Zorzano A, Palacin M. Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J Biol Chem. 1999 Jul 9;274(28):19738-44. PMID:10391915
↑ Rossier G, Meier C, Bauch C, Summa V, Sordat B, Verrey F, Kuhn LC. LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine. J Biol Chem. 1999 Dec 3;274(49):34948-54. PMID:10574970
↑ Broer A, Friedrich B, Wagner CA, Fillon S, Ganapathy V, Lang F, Broer S. Association of 4F2hc with light chains LAT1, LAT2 or y+LAT2 requires different domains. Biochem J. 2001 May 1;355(Pt 3):725-31. PMID:11311135
↑ Ritchie JW, Taylor PM. Role of the System L permease LAT1 in amino acid and iodothyronine transport in placenta. Biochem J. 2001 Jun 15;356(Pt 3):719-25. PMID:11389679
↑ Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, Cha SH, Matsuo H, Fukushima J, Fukasawa Y, Tani Y, Taketani Y, Uchino H, Kim JY, Inatomi J, Okayasu I, Miyamoto K, Takeda E, Goya T, Endou H. Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta. 2001 Oct 1;1514(2):291-302. PMID:11557028
↑ Friesema EC, Docter R, Moerings EP, Verrey F, Krenning EP, Hennemann G, Visser TJ. Thyroid hormone transport by the heterodimeric human system L amino acid transporter. Endocrinology. 2001 Oct;142(10):4339-48. PMID:11564694
↑ Okamoto Y, Sakata M, Ogura K, Yamamoto T, Yamaguchi M, Tasaka K, Kurachi H, Tsurudome M, Murata Y. Expression and regulation of 4F2hc and hLAT1 in human trophoblasts. Am J Physiol Cell Physiol. 2002 Jan;282(1):C196-204. PMID:11742812
↑ Simmons-Willis TA, Koh AS, Clarkson TW, Ballatori N. Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. Biochem J. 2002 Oct 1;367(Pt 1):239-46. PMID:12117417 doi:http://dx.doi.org/10.1042/BJ20020841
↑ Kim DK, Kanai Y, Choi HW, Tangtrongsup S, Chairoungdua A, Babu E, Tachampa K, Anzai N, Iribe Y, Endou H. Characterization of the system L amino acid transporter in T24 human bladder carcinoma cells. Biochim Biophys Acta. 2002 Sep 20;1565(1):112-21. PMID:12225859
↑ Li S, Whorton AR. Identification of stereoselective transporters for S-nitroso-L-cysteine: role of LAT1 and LAT2 in biological activity of S-nitrosothiols. J Biol Chem. 2005 May 20;280(20):20102-10. Epub 2005 Mar 15. PMID:15769744 doi:http://dx.doi.org/10.1074/jbc.M413164200
↑ Nawashiro H, Otani N, Shinomiya N, Fukui S, Ooigawa H, Shima K, Matsuo H, Kanai Y, Endou H. L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors. Int J Cancer. 2006 Aug 1;119(3):484-92. doi: 10.1002/ijc.21866. PMID:16496379 doi:http://dx.doi.org/10.1002/ijc.21866
↑ Vumma R, Wiesel FA, Flyckt L, Bjerkenstedt L, Venizelos N. Functional characterization of tyrosine transport in fibroblast cells from healthy controls. Neurosci Lett. 2008 Mar 21;434(1):56-60. doi: 10.1016/j.neulet.2008.01.028. Epub , 2008 Jan 17. PMID:18262359 doi:http://dx.doi.org/10.1016/j.neulet.2008.01.028
↑ Milkereit R, Persaud A, Vanoaica L, Guetg A, Verrey F, Rotin D. LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation. Nat Commun. 2015 May 22;6:7250. doi: 10.1038/ncomms8250. PMID:25998567 doi:http://dx.doi.org/10.1038/ncomms8250
↑ Mastroberardino L, Spindler B, Pfeiffer R, Skelly PJ, Loffing J, Shoemaker CB, Verrey F. Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature. 1998 Sep 17;395(6699):288-91. PMID:9751058 doi:http://dx.doi.org/10.1038/26246
↑ Lee Y, Wiriyasermkul P, Jin C, Quan L, Ohgaki R, Okuda S, Kusakizako T, Nishizawa T, Oda K, Ishitani R, Yokoyama T, Nakane T, Shirouzu M, Endou H, Nagamori S, Kanai Y, Nureki O. Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc. Nat Struct Mol Biol. 2019 Jun;26(6):510-517. doi: 10.1038/s41594-019-0237-7. Epub, 2019 Jun 3. PMID:31160781 doi:http://dx.doi.org/10.1038/s41594-019-0237-7

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6jmq"

@@ Line 1: / Line 1: @@
 ==LAT1-CD98hc complex bound to MEM-108 Fab==
-<StructureSection load='6jmq' size='340' side='right'caption='[[6jmq]], [[Resolution|resolution]] 3.31&Aring;' scene=''>
+<SX load='6jmq' size='340' side='right' viewer='molstar' caption='[[6jmq]], [[Resolution|resolution]] 3.31&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6jmq]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JMQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6JMQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6jmq]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JMQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JMQ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.31&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=UNK:UNKNOWN'>UNK</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SLC7A5, CD98LC, LAT1, MPE16 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), SLC3A2, MDU1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6jmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jmq OCA], [https://pdbe.org/6jmq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jmq RCSB], [https://www.ebi.ac.uk/pdbsum/6jmq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jmq ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6jmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jmq OCA], [http://pdbe.org/6jmq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jmq RCSB], [http://www.ebi.ac.uk/pdbsum/6jmq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jmq ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/LAT1_HUMAN LAT1_HUMAN]] Sodium-independent, high-affinity transport of large neutral amino acids such as phenylalanine, tyrosine, leucine, arginine and tryptophan, when associated with SLC3A2/4F2hc. Involved in cellular amino acid uptake. Acts as an amino acid exchanger. Involved in the transport of L-DOPA across the blood-brain barrier, and that of thyroid hormones triiodothyronine (T3) and thyroxine (T4) across the cell membrane in tissues such as placenta. Plays a role in neuronal cell proliferation (neurogenesis) in brain. Involved in the uptake of methylmercury (MeHg) when administered as the L-cysteine or D,L-homocysteine complexes, and hence plays a role in metal ion homeostasis and toxicity. Involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the transmembrane. May play an important role in high-grade gliomas. Mediates blood-to-retina L-leucine transport across the inner blood-retinal barrier which in turn may play a key role in maintaining large neutral amino acids as well as neurotransmitters in the neural retina. Acts as the major transporter of tyrosine in fibroblasts. When associated with LAPTM4B, recruits SLC3A2 and SLC7A5 to lysosomes to promote leucine uptake into these organelles and is required for mTORC1 activation (PubMed:25998567).<ref>PMID:10049700</ref> <ref>PMID:10391915</ref> <ref>PMID:10574970</ref> <ref>PMID:11311135</ref> <ref>PMID:11389679</ref> <ref>PMID:11557028</ref> <ref>PMID:11564694</ref> <ref>PMID:11742812</ref> <ref>PMID:12117417</ref> <ref>PMID:12225859</ref> <ref>PMID:15769744</ref> <ref>PMID:16496379</ref> <ref>PMID:18262359</ref> <ref>PMID:25998567</ref> <ref>PMID:9751058</ref>  [[http://www.uniprot.org/uniprot/4F2_HUMAN 4F2_HUMAN]] Required for the function of light chain amino-acid transporters. Involved in sodium-independent, high-affinity transport of large neutral amino acids such as phenylalanine, tyrosine, leucine, arginine and tryptophan. Involved in guiding and targeting of LAT1 and LAT2 to the plasma membrane. When associated with SLC7A6 or SLC7A7 acts as an arginine/glutamine exchanger, following an antiport mechanism for amino acid transport, influencing arginine release in exchange for extracellular amino acids. Plays a role in nitric oxide synthesis in human umbilical vein endothelial cells (HUVECs) via transport of L-arginine. Required for normal and neoplastic cell growth. When associated with SLC7A5/LAT1, is also involved in the transport of L-DOPA across the blood-brain barrier, and that of thyroid hormones triiodothyronine (T3) and thyroxine (T4) across the cell membrane in tissues such as placenta. Involved in the uptake of methylmercury (MeHg) when administered as the L-cysteine or D,L-homocysteine complexes, and hence plays a role in metal ion homeostasis and toxicity. When associated with SLC7A5 or SLC7A8, involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the transmembrane. Together with ICAM1, regulates the transport activity LAT2 in polarized intestinal cells, by generating and delivering intracellular signals. When associated with SLC7A5, plays an important role in transporting L-leucine from the circulating blood to the retina across the inner blood-retinal barrier.<ref>PMID:11557028</ref> <ref>PMID:9829974</ref> <ref>PMID:9751058</ref> <ref>PMID:9878049</ref> <ref>PMID:10903140</ref> <ref>PMID:11311135</ref> <ref>PMID:11389679</ref> <ref>PMID:11564694</ref> <ref>PMID:11742812</ref> <ref>PMID:12117417</ref> <ref>PMID:12225859</ref> <ref>PMID:14603368</ref> <ref>PMID:12716892</ref> <ref>PMID:15980244</ref> <ref>PMID:15769744</ref>
+[https://www.uniprot.org/uniprot/LAT1_HUMAN LAT1_HUMAN] Sodium-independent, high-affinity transport of large neutral amino acids such as phenylalanine, tyrosine, leucine, arginine and tryptophan, when associated with SLC3A2/4F2hc. Involved in cellular amino acid uptake. Acts as an amino acid exchanger. Involved in the transport of L-DOPA across the blood-brain barrier, and that of thyroid hormones triiodothyronine (T3) and thyroxine (T4) across the cell membrane in tissues such as placenta. Plays a role in neuronal cell proliferation (neurogenesis) in brain. Involved in the uptake of methylmercury (MeHg) when administered as the L-cysteine or D,L-homocysteine complexes, and hence plays a role in metal ion homeostasis and toxicity. Involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the transmembrane. May play an important role in high-grade gliomas. Mediates blood-to-retina L-leucine transport across the inner blood-retinal barrier which in turn may play a key role in maintaining large neutral amino acids as well as neurotransmitters in the neural retina. Acts as the major transporter of tyrosine in fibroblasts. When associated with LAPTM4B, recruits SLC3A2 and SLC7A5 to lysosomes to promote leucine uptake into these organelles and is required for mTORC1 activation (PubMed:25998567).<ref>PMID:10049700</ref> <ref>PMID:10391915</ref> <ref>PMID:10574970</ref> <ref>PMID:11311135</ref> <ref>PMID:11389679</ref> <ref>PMID:11557028</ref> <ref>PMID:11564694</ref> <ref>PMID:11742812</ref> <ref>PMID:12117417</ref> <ref>PMID:12225859</ref> <ref>PMID:15769744</ref> <ref>PMID:16496379</ref> <ref>PMID:18262359</ref> <ref>PMID:25998567</ref> <ref>PMID:9751058</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 6jmq" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Antibody 3D structures|Antibody 3D structures]]
+*[[3D structures of non-human antibody|3D structures of non-human antibody]]
 == References ==
 <references/>
 __TOC__
-</StructureSection>
+</SX>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Lk3 transgenic mice]]
+[[Category: Mus musculus]]
-[[Category: Ishitani, R]]
+[[Category: Ishitani R]]
-[[Category: Kusakizako, T]]
+[[Category: Kusakizako T]]
-[[Category: Lee, Y]]
+[[Category: Lee Y]]
-[[Category: Nakane, T]]
+[[Category: Nakane T]]
-[[Category: Nishizawa, T]]
+[[Category: Nishizawa T]]
-[[Category: Nureki, O]]
+[[Category: Nureki O]]
-[[Category: Oda, K]]
+[[Category: Oda K]]
-[[Category: Complex]]
-[[Category: Glycoprotein]]
-[[Category: Membrane protein]]
-[[Category: Membrane protein-immune system complex]]
-[[Category: Transporter]]

6jmq

From Proteopedia

Current revision

LAT1-CD98hc complex bound to MEM-108 Fab

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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