4yn0 | pdb_00004yn0

Crystal structure of APP E2 domain in complex with DR6 CRD domain

Structural highlights

4yn0 is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2Å
Ligands:	MG, NAG
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TNR21_MOUSE Promotes apoptosis, possibly via a pathway that involves the activation of NF-kappa-B. Can also promote apoptosis mediated by BAX and by the release of cytochrome c from the mitochondria into the cytoplasm. Plays a role in neuronal apoptosis, including apoptosis in response to amyloid peptides derived from APP, and is required for both normal cell body death and axonal pruning. Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP). N-APP binds TNFRSF21; this triggers caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6). Negatively regulates oligodendrocyte survival, maturation and myelination. Plays a role in signaling cascades triggered by stimulation of T-cell receptors, in the adaptive immune response and in the regulation of T-cell differentiation and proliferation. Negatively regulates T-cell responses and the release of cytokines such as IL4, IL5, IL10, IL13 and IFNG by Th2 cells. Negatively regulates the production of IgG, IgM and IgM in response to antigens. May inhibit the activation of JNK in response to T-cell stimulation.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

The amyloid precursor protein (APP) has garnered considerable attention due to its genetic links to Alzheimer's disease. Death receptor 6 (DR6) was recently shown to bind APP via the protein extracellular regions, stimulate axonal pruning, and inhibit synapse formation. Here, we report the crystal structure of the DR6 ectodomain in complex with the E2 domain of APP and show that it supports a model for APP-induced dimerization and activation of cell surface DR6.

The crystal structure of DR6 in complex with the amyloid precursor protein provides insight into death receptor activation.,Xu K, Olsen O, Tzvetkova-Robev D, Tessier-Lavigne M, Nikolov DB Genes Dev. 2015 Apr 2. PMID:25838500^[7]

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

References

↑ Liu J, Na S, Glasebrook A, Fox N, Solenberg PJ, Zhang Q, Song HY, Yang DD. Enhanced CD4+ T cell proliferation and Th2 cytokine production in DR6-deficient mice. Immunity. 2001 Jul;15(1):23-34. PMID:11485735
↑ Zhao H, Yan M, Wang H, Erickson S, Grewal IS, Dixit VM. Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice. J Exp Med. 2001 Nov 19;194(10):1441-8. PMID:11714751
↑ Schmidt CS, Liu J, Zhang T, Song HY, Sandusky G, Mintze K, Benschop RJ, Glasebrook A, Yang DD, Na S. Enhanced B cell expansion, survival, and humoral responses by targeting death receptor 6. J Exp Med. 2003 Jan 6;197(1):51-62. PMID:12515813
↑ Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PMID:19225519 doi:10.1038/nature07767
↑ Mi S, Lee X, Hu Y, Ji B, Shao Z, Yang W, Huang G, Walus L, Rhodes K, Gong BJ, Miller RH, Pepinsky RB. Death receptor 6 negatively regulates oligodendrocyte survival, maturation and myelination. Nat Med. 2011 Jul 3;17(7):816-21. doi: 10.1038/nm.2373. PMID:21725297 doi:https://dx.doi.org/10.1038/nm.2373
↑ Hu Y, Lee X, Shao Z, Apicco D, Huang G, Gong BJ, Pepinsky RB, Mi S. A DR6/p75(NTR) complex is responsible for beta-amyloid-induced cortical neuron death. Cell Death Dis. 2013 Apr 4;4:e579. doi: 10.1038/cddis.2013.110. PMID:23559013 doi:https://dx.doi.org/10.1038/cddis.2013.110
↑ Xu K, Olsen O, Tzvetkova-Robev D, Tessier-Lavigne M, Nikolov DB. The crystal structure of DR6 in complex with the amyloid precursor protein provides insight into death receptor activation. Genes Dev. 2015 Apr 2. PMID:25838500 doi:https://dx.doi.org/10.1101/gad.257675.114

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Liu J, Na S, Glasebrook A, Fox N, Solenberg PJ, Zhang Q, Song HY, Yang DD. Enhanced CD4+ T cell proliferation and Th2 cytokine production in DR6-deficient mice. Immunity. 2001 Jul;15(1):23-34. PMID:11485735

[2] Zhao H, Yan M, Wang H, Erickson S, Grewal IS, Dixit VM. Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice. J Exp Med. 2001 Nov 19;194(10):1441-8. PMID:11714751

[3] Schmidt CS, Liu J, Zhang T, Song HY, Sandusky G, Mintze K, Benschop RJ, Glasebrook A, Yang DD, Na S. Enhanced B cell expansion, survival, and humoral responses by targeting death receptor 6. J Exp Med. 2003 Jan 6;197(1):51-62. PMID:12515813

[4] Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PMID:19225519 doi:10.1038/nature07767

[5] Mi S, Lee X, Hu Y, Ji B, Shao Z, Yang W, Huang G, Walus L, Rhodes K, Gong BJ, Miller RH, Pepinsky RB. Death receptor 6 negatively regulates oligodendrocyte survival, maturation and myelination. Nat Med. 2011 Jul 3;17(7):816-21. doi: 10.1038/nm.2373. PMID:21725297 doi:https://dx.doi.org/10.1038/nm.2373

[6] Hu Y, Lee X, Shao Z, Apicco D, Huang G, Gong BJ, Pepinsky RB, Mi S. A DR6/p75(NTR) complex is responsible for beta-amyloid-induced cortical neuron death. Cell Death Dis. 2013 Apr 4;4:e579. doi: 10.1038/cddis.2013.110. PMID:23559013 doi:https://dx.doi.org/10.1038/cddis.2013.110

[7] Xu K, Olsen O, Tzvetkova-Robev D, Tessier-Lavigne M, Nikolov DB. The crystal structure of DR6 in complex with the amyloid precursor protein provides insight into death receptor activation. Genes Dev. 2015 Apr 2. PMID:25838500 doi:https://dx.doi.org/10.1101/gad.257675.114

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4yn0 | pdb_00004yn0

Crystal structure of APP E2 domain in complex with DR6 CRD domain

Structural highlights

Function

Publication Abstract from PubMed

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References

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