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4cud

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Revision as of 10:00, 5 February 2020

Human Notch1 EGF domains 11-13 mutant fucosylated at T466

Structural highlights

4cud is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	4cue, 4cuf
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[NOTC1_HUMAN] Defects in NOTCH1 are a cause of aortic valve disease 1 (AOVD1) [MIM:109730]. A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome.^[1]

Function

[NOTC1_HUMAN] Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. May be important for normal lymphocyte function. In altered form, may contribute to transformation or progression in some T-cell neoplasms. Involved in the maturation of both CD4+ and CD8+ cells in the thymus. May be important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, may function as a receptor for neuronal DNER and may be involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May enhance HIF1A function by sequestering HIF1AN away from HIF1A (By similarity).

Publication Abstract from PubMed

The Notch signaling pathway is essential for many aspects of development, cell fate determination, and tissue homeostasis. Notch signaling can be modulated by posttranslational modifications to the Notch receptor, which are known to alter both ligand binding and receptor activation. We have modified the ligand-binding region (EGF domains 11-13) of human Notch1 (hN1) with O-fucose and O-glucose glycans and shown by flow cytometry and surface plasmon resonance that the Fringe-catalyzed addition of GlcNAc to the O-fucose at T466 in EGF12 substantially increases binding to Jagged1 and Delta-like 1 (DLL1) ligands. We have subsequently determined the crystal structures of EGF domains 11-13 of hN1 modified with either the O-fucose monosaccharide or the GlcNAc-fucose disaccharide at T466 of EGF12 and observed no change in backbone structure for each variant. Collectively, these data demonstrate a role for GlcNAc in modulating the ligand-binding site in hN1 EGF12, resulting in an increased affinity of this region for ligands Jagged1 and DLL1. We propose that this finding explains the Fringe-catalyzed enhancement of Notch-Delta signaling observed in flies and humans, but suggest that the inhibitory effect of Fringe on Jagged/Serrate mediated signaling involves other regions of Notch.

Fringe-mediated extension of O-linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands.,Taylor P, Takeuchi H, Sheppard D, Chillakuri C, Lea SM, Haltiwanger RS, Handford PA Proc Natl Acad Sci U S A. 2014 May 6. PMID:24803430^[2]

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

References

↑ Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005 Sep 8;437(7056):270-4. Epub 2005 Jul 17. PMID:16025100 doi:10.1038/nature03940
↑ Taylor P, Takeuchi H, Sheppard D, Chillakuri C, Lea SM, Haltiwanger RS, Handford PA. Fringe-mediated extension of O-linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands. Proc Natl Acad Sci U S A. 2014 May 6. PMID:24803430 doi:http://dx.doi.org/10.1073/pnas.1319683111

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/4cud"

@@ Line 1: / Line 1: @@
 ==Human Notch1 EGF domains 11-13 mutant fucosylated at T466==
-<StructureSection load='4cud' size='340' side='right' caption='[[4cud]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
+<StructureSection load='4cud' size='340' side='right'caption='[[4cud]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4cud]] is a 1 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=4CUD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CUD FirstGlance]. <br>
@@ Line 26: / Line 26: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Chillakuri, C]]
 [[Category: Haltiwanger, R S]]

4cud

From Proteopedia

Revision as of 10:00, 5 February 2020

Human Notch1 EGF domains 11-13 mutant fucosylated at T466

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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