4mxw: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Structure of heterotrimeric lymphotoxin LTa1b2 bound to lymphotoxin beta receptor LTbR and anti-LTa Fab== | |||
<StructureSection load='4mxw' size='340' side='right' caption='[[4mxw]], [[Resolution|resolution]] 3.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4mxw]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MXW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MXW FirstGlance]. <br> | |||
==Disease== | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mxv|4mxv]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LTBR, D12S370, TNFCR, TNFR3, TNFRSF3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), LTA, TNFB, TNFSF1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), LTB, TNFC, TNFSF3 ([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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mxw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mxw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mxw RCSB], [http://www.ebi.ac.uk/pdbsum/4mxw PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/TNFB_HUMAN TNFB_HUMAN]] Genetic variations in LTA are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:[http://omim.org/entry/607507 607507]]. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). | [[http://www.uniprot.org/uniprot/TNFB_HUMAN TNFB_HUMAN]] Genetic variations in LTA are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:[http://omim.org/entry/607507 607507]]. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/TNR3_HUMAN TNR3_HUMAN]] Receptor for the heterotrimeric lymphotoxin containing LTA and LTB, and for TNFS14/LIGHT. Promotes apoptosis via TRAF3 and TRAF5. May play a role in the development of lymphoid organs.<ref>PMID:8171323</ref> <ref>PMID:10799510</ref> [[http://www.uniprot.org/uniprot/TNFC_HUMAN TNFC_HUMAN]] Cytokine that binds to LTBR/TNFRSF3. May play a specific role in immune response regulation. Provides the membrane anchor for the attachment of the heterotrimeric complex to the cell surface. Isoform 2 is probably non-functional. [[http://www.uniprot.org/uniprot/TNFB_HUMAN TNFB_HUMAN]] Cytokine that in its homotrimeric form binds to TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM. In its heterotrimeric form with LTB binds to TNFRSF3/LTBR. Lymphotoxin is produced by lymphocytes and cytotoxic for a wide range of tumor cells in vitro and in vivo. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Homotrimeric TNF superfamily ligands signal by inducing trimers of their cognate receptors. As a biologically active heterotrimer, Lymphotoxin(LT)alpha1beta2 is unique in the TNF superfamily. How the three unique potential receptor-binding interfaces in LTalpha1beta2 trigger signaling via LTbeta Receptor (LTbetaR) resulting in lymphoid organogenesis and propagation of inflammatory signals is poorly understood. Here we show that LTalpha1beta2 possesses two binding sites for LTbetaR with distinct affinities and that dimerization of LTbetaR by LTalpha1beta2 is necessary and sufficient for signal transduction. The crystal structure of a complex formed by LTalpha1beta2, LTbetaR, and the fab fragment of an antibody that blocks LTbetaR activation reveals the lower affinity receptor-binding site. Mutations targeting each potential receptor-binding site in an engineered single-chain variant of LTalpha1beta2 reveal the high-affinity site. NF-kappaB reporter assays further validate that disruption of receptor interactions at either site is sufficient to prevent signaling via LTbetaR. | |||
Dimerization of LTbetaR by LTalpha1beta2 is necessary and sufficient for signal transduction.,Sudhamsu J, Yin J, Chiang EY, Starovasnik MA, Grogan JL, Hymowitz SG Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19896-901. doi:, 10.1073/pnas.1310838110. Epub 2013 Nov 18. PMID:24248355<ref>PMID:24248355</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Monoclonal Antibody|Monoclonal Antibody]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Hymowitz, S G | [[Category: Hymowitz, S G]] | ||
[[Category: Sudhamsu, J | [[Category: Sudhamsu, J]] | ||
[[Category: Yin, J P | [[Category: Yin, J P]] | ||
[[Category: Auto-immunity]] | [[Category: Auto-immunity]] | ||
[[Category: Cytokine-immune system complex]] | [[Category: Cytokine-immune system complex]] | ||
Revision as of 20:33, 21 December 2014
Structure of heterotrimeric lymphotoxin LTa1b2 bound to lymphotoxin beta receptor LTbR and anti-LTa FabStructure of heterotrimeric lymphotoxin LTa1b2 bound to lymphotoxin beta receptor LTbR and anti-LTa Fab
Structural highlights
Disease[TNFB_HUMAN] Genetic variations in LTA are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:607507]. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). Function[TNR3_HUMAN] Receptor for the heterotrimeric lymphotoxin containing LTA and LTB, and for TNFS14/LIGHT. Promotes apoptosis via TRAF3 and TRAF5. May play a role in the development of lymphoid organs.[1] [2] [TNFC_HUMAN] Cytokine that binds to LTBR/TNFRSF3. May play a specific role in immune response regulation. Provides the membrane anchor for the attachment of the heterotrimeric complex to the cell surface. Isoform 2 is probably non-functional. [TNFB_HUMAN] Cytokine that in its homotrimeric form binds to TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM. In its heterotrimeric form with LTB binds to TNFRSF3/LTBR. Lymphotoxin is produced by lymphocytes and cytotoxic for a wide range of tumor cells in vitro and in vivo. Publication Abstract from PubMedHomotrimeric TNF superfamily ligands signal by inducing trimers of their cognate receptors. As a biologically active heterotrimer, Lymphotoxin(LT)alpha1beta2 is unique in the TNF superfamily. How the three unique potential receptor-binding interfaces in LTalpha1beta2 trigger signaling via LTbeta Receptor (LTbetaR) resulting in lymphoid organogenesis and propagation of inflammatory signals is poorly understood. Here we show that LTalpha1beta2 possesses two binding sites for LTbetaR with distinct affinities and that dimerization of LTbetaR by LTalpha1beta2 is necessary and sufficient for signal transduction. The crystal structure of a complex formed by LTalpha1beta2, LTbetaR, and the fab fragment of an antibody that blocks LTbetaR activation reveals the lower affinity receptor-binding site. Mutations targeting each potential receptor-binding site in an engineered single-chain variant of LTalpha1beta2 reveal the high-affinity site. NF-kappaB reporter assays further validate that disruption of receptor interactions at either site is sufficient to prevent signaling via LTbetaR. Dimerization of LTbetaR by LTalpha1beta2 is necessary and sufficient for signal transduction.,Sudhamsu J, Yin J, Chiang EY, Starovasnik MA, Grogan JL, Hymowitz SG Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19896-901. doi:, 10.1073/pnas.1310838110. Epub 2013 Nov 18. PMID:24248355[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||