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4i9x

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Revision as of 08:07, 27 March 2019

Crystal structure of human cytomegalovirus glycoprotein UL141 targeting the death receptor TRAIL-R2

Structural highlights

4i9x is a 4 chain structure with sequence from Hcmvm and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
NonStd Res:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[TR10B_HUMAN] Defects in TNFRSF10B may be a cause of head and neck squamous cell carcinomas (HNSCC) [MIM:275355]; also known as squamous cell carcinoma of the head and neck.

Function

[UL141_HCMVM] Evasion of NK cell killing. Blocks surface expression of PVR which is a ligand for NK cell-activating receptors. Binds human PVR in the endoplasmic reticulum and prevents its maturation and transport to the cell surface. Targets also the natural killer cell activating ligand PVRL2/Nectin-2 for proteasome-mediated degradation.^[1] [TR10B_HUMAN] Receptor for the cytotoxic ligand TNFSF10/TRAIL. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Promotes the activation of NF-kappa-B. Essential for ER stress-induced apoptosis.^[2]

Publication Abstract from PubMed

The TRAIL (TNF-related apoptosis inducing ligand) death receptors (DRs) of the tumor necrosis factor receptor superfamily (TNFRSF) can promote apoptosis and regulate antiviral immunity by maintaining immune homeostasis during infection. In turn, human cytomegalovirus (HCMV) expresses immunomodulatory proteins that down-regulate cell surface expression of TNFRSF members as well as poliovirus receptor-related proteins in an effort to inhibit host immune effector pathways that would lead to viral clearance. The UL141 glycoprotein of human cytomegalovirus inhibits host defenses by blocking cell surface expression of TRAIL DRs (by retention in ER) and poliovirus receptor CD155, a nectin-like Ig-fold molecule. Here we show that the immunomodulatory function of HCMV UL141 is associated with its ability to bind diverse proteins, while utilizing at least two distinct binding sites to selectively engage TRAIL DRs or CD155. Binding studies revealed high affinity interaction of UL141 with both TRAIL-R2 and CD155 and low affinity binding to TRAIL-R1. We determined the crystal structure of UL141 bound to TRAIL-R2 at 2.1 A resolution, which revealed that UL141 forms a homodimer that engages two TRAIL-R2 monomers 90 degrees apart to form a heterotetrameric complex. Our structural and biochemical data reveal that UL141 utilizes its Ig-domain to facilitate non-canonical death receptor interactions while UL141 partially mimics the binding site of TRAIL on TRAIL-R2, which we found to be distinct from that of CD155. Moreover, UL141 also binds to an additional surface patch on TRAIL-R2 that is distinct from the TRAIL binding site. Therefore, the breadth of UL141-mediated effects indicates that HCMV has evolved sophisticated strategies to evade the immune system by modulating multiple effector pathways.

Structure of Human Cytomegalovirus UL141 Binding to TRAIL-R2 Reveals Novel, Non-canonical Death Receptor Interactions.,Nemcovicova I, Benedict CA, Zajonc DM PLoS Pathog. 2013 Mar;9(3):e1003224. doi: 10.1371/journal.ppat.1003224. Epub 2013, Mar 21. PMID:23555243^[3]

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

References

↑ Prod'homme V, Sugrue DM, Stanton RJ, Nomoto A, Davies J, Rickards CR, Cochrane D, Moore M, Wilkinson GW, Tomasec P. Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112. J Gen Virol. 2010 Aug;91(Pt 8):2034-9. doi: 10.1099/vir.0.021931-0. Epub 2010 Apr, 21. PMID:20410314 doi:http://dx.doi.org/10.1099/vir.0.021931-0
↑ Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem. 2004 Oct 29;279(44):45495-502. Epub 2004 Aug 18. PMID:15322075 doi:10.1074/jbc.M406933200
↑ Nemcovicova I, Benedict CA, Zajonc DM. Structure of Human Cytomegalovirus UL141 Binding to TRAIL-R2 Reveals Novel, Non-canonical Death Receptor Interactions. PLoS Pathog. 2013 Mar;9(3):e1003224. doi: 10.1371/journal.ppat.1003224. Epub 2013, Mar 21. PMID:23555243 doi:http://dx.doi.org/10.1371/journal.ppat.1003224

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4i9x"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human cytomegalovirus glycoprotein UL141 targeting the death receptor TRAIL-R2==
-<StructureSection load='4i9x' size='340' side='right' caption='[[4i9x]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+<StructureSection load='4i9x' size='340' side='right'caption='[[4i9x]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4i9x]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Hcmvm Hcmvm] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I9X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I9X FirstGlance]. <br>
@@ Line 30: / Line 30: @@
 [[Category: Hcmvm]]
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Nemcovicova, I]]
 [[Category: Zajonc, D M]]
 [[Category: Apoptosis]]
 [[Category: Ig-like domain]]

4i9x

From Proteopedia

Revision as of 08:07, 27 March 2019

Crystal structure of human cytomegalovirus glycoprotein UL141 targeting the death receptor TRAIL-R2

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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