4cc1: Difference between revisions

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New page: '''Unreleased structure''' The entry 4cc1 is ON HOLD until Paper Publication Authors: Chilakuri, C., Sheppard, D., Ilagan, M., Holt, L., Abbott, F., Liang, S., Kopan, R., Handford, P., ...
 
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'''Unreleased structure'''


The entry 4cc1 is ON HOLD  until Paper Publication
==Notch ligand, Jagged-1, contains an N-terminal C2 domain==
<StructureSection load='4cc1' size='340' side='right'caption='[[4cc1]], [[Resolution|resolution]] 2.84&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4cc1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CC1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CC1 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.84&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=4cc1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cc1 OCA], [https://pdbe.org/4cc1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cc1 RCSB], [https://www.ebi.ac.uk/pdbsum/4cc1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cc1 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/JAG1_HUMAN JAG1_HUMAN] Defects in JAG1 are the cause of Alagille syndrome type 1 (ALGS1) [MIM:[https://omim.org/entry/118450 118450]. Alagille syndrome is an autosomal dominant multisystem disorder defined clinically by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. There are characteristic facial features and less frequent clinical involvement of the renal and vascular systems.<ref>PMID:9207788</ref> <ref>PMID:9207787</ref> <ref>PMID:9585603</ref> <ref>PMID:10220506</ref> <ref>PMID:10533065</ref> <ref>PMID:11058898</ref> <ref>PMID:11157803</ref> <ref>PMID:11139247</ref> <ref>PMID:11180599</ref> <ref>PMID:12442286</ref> <ref>PMID:12497640</ref> <ref>PMID:15712272</ref> <ref>PMID:16575836</ref>  Defects in JAG1 are a cause of tetralogy of Fallot (TOF) [MIM:[https://omim.org/entry/187500 187500]. TOF is a congenital heart anomaly which consists of pulmonary stenosis, ventricular septal defect, dextroposition of the aorta (aorta is on the right side instead of the left) and hypertrophy of the right ventricle. This condition results in a blue baby at birth due to inadequate oxygenation. Surgical correction is emergent.<ref>PMID:9207787</ref> <ref>PMID:11152664</ref>
== Function ==
[https://www.uniprot.org/uniprot/JAG1_HUMAN JAG1_HUMAN] Ligand for multiple Notch receptors and involved in the mediation of Notch signaling. May be involved in cell-fate decisions during hematopoiesis. Seems to be involved in early and late stages of mammalian cardiovascular development. Inhibits myoblast differentiation (By similarity). Enhances fibroblast growth factor-induced angiogenesis (in vitro).<ref>PMID:9462510</ref> <ref>PMID:18660822</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The Notch pathway is a core cell-cell signaling system in metazoan organisms with key roles in cell-fate determination, stem cell maintenance, immune system activation, and angiogenesis. Signals are initiated by extracellular interactions of the Notch receptor with Delta/Serrate/Lag-2 (DSL) ligands, whose structure is highly conserved throughout evolution. To date, no structure or activity has been associated with the extreme N termini of the ligands, even though numerous mutations in this region of Jagged-1 ligand lead to human disease. Here, we demonstrate that the N terminus of human Jagged-1 is a C2 phospholipid recognition domain that binds phospholipid bilayers in a calcium-dependent fashion. Furthermore, we show that this activity is shared by a member of the other class of Notch ligands, human Delta-like-1, and the evolutionary distant Drosophila Serrate. Targeted mutagenesis of Jagged-1 C2 domain residues implicated in calcium-dependent phospholipid binding leaves Notch interactions intact but can reduce Notch activation. These results reveal an important and previously unsuspected role for phospholipid recognition in control of this key signaling system.


Authors: Chilakuri, C., Sheppard, D., Ilagan, M., Holt, L., Abbott, F., Liang, S., Kopan, R., Handford, P., Lea, S.
Structural Analysis Uncovers Lipid-Binding Properties of Notch Ligands.,Chillakuri CR, Sheppard D, Ilagan MX, Holt LR, Abbott F, Liang S, Kopan R, Handford PA, Lea SM Cell Rep. 2013 Nov 13. pii: S2211-1247(13)00613-X. doi:, 10.1016/j.celrep.2013.10.029. PMID:24239355<ref>PMID:24239355</ref>


Description: Notch ligand, Jagged-1, contains an N-terminal C2 domain
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4cc1" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Abbott F]]
[[Category: Chilakuri CR]]
[[Category: Handford PA]]
[[Category: Holt LR]]
[[Category: Ilagan MXG]]
[[Category: Kopan R]]
[[Category: Lea SM]]
[[Category: Liang S]]
[[Category: Sheppard D]]

Latest revision as of 15:07, 20 December 2023

Notch ligand, Jagged-1, contains an N-terminal C2 domainNotch ligand, Jagged-1, contains an N-terminal C2 domain

Structural highlights

4cc1 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.84Å
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

JAG1_HUMAN Defects in JAG1 are the cause of Alagille syndrome type 1 (ALGS1) [MIM:118450. Alagille syndrome is an autosomal dominant multisystem disorder defined clinically by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. There are characteristic facial features and less frequent clinical involvement of the renal and vascular systems.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Defects in JAG1 are a cause of tetralogy of Fallot (TOF) [MIM:187500. TOF is a congenital heart anomaly which consists of pulmonary stenosis, ventricular septal defect, dextroposition of the aorta (aorta is on the right side instead of the left) and hypertrophy of the right ventricle. This condition results in a blue baby at birth due to inadequate oxygenation. Surgical correction is emergent.[14] [15]

Function

JAG1_HUMAN Ligand for multiple Notch receptors and involved in the mediation of Notch signaling. May be involved in cell-fate decisions during hematopoiesis. Seems to be involved in early and late stages of mammalian cardiovascular development. Inhibits myoblast differentiation (By similarity). Enhances fibroblast growth factor-induced angiogenesis (in vitro).[16] [17]

Publication Abstract from PubMed

The Notch pathway is a core cell-cell signaling system in metazoan organisms with key roles in cell-fate determination, stem cell maintenance, immune system activation, and angiogenesis. Signals are initiated by extracellular interactions of the Notch receptor with Delta/Serrate/Lag-2 (DSL) ligands, whose structure is highly conserved throughout evolution. To date, no structure or activity has been associated with the extreme N termini of the ligands, even though numerous mutations in this region of Jagged-1 ligand lead to human disease. Here, we demonstrate that the N terminus of human Jagged-1 is a C2 phospholipid recognition domain that binds phospholipid bilayers in a calcium-dependent fashion. Furthermore, we show that this activity is shared by a member of the other class of Notch ligands, human Delta-like-1, and the evolutionary distant Drosophila Serrate. Targeted mutagenesis of Jagged-1 C2 domain residues implicated in calcium-dependent phospholipid binding leaves Notch interactions intact but can reduce Notch activation. These results reveal an important and previously unsuspected role for phospholipid recognition in control of this key signaling system.

Structural Analysis Uncovers Lipid-Binding Properties of Notch Ligands.,Chillakuri CR, Sheppard D, Ilagan MX, Holt LR, Abbott F, Liang S, Kopan R, Handford PA, Lea SM Cell Rep. 2013 Nov 13. pii: S2211-1247(13)00613-X. doi:, 10.1016/j.celrep.2013.10.029. PMID:24239355[18]

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

References

  1. ↑ Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997 Jul;16(3):243-51. PMID:9207788 doi:10.1038/ng0797-243
  2. ↑ Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997 Jul;16(3):235-42. PMID:9207787 doi:10.1038/ng0797-235
  3. ↑ Krantz ID, Colliton RP, Genin A, Rand EB, Li L, Piccoli DA, Spinner NB. Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet. 1998 Jun;62(6):1361-9. PMID:9585603 doi:S0002-9297(07)62777-3
  4. ↑ Crosnier C, Driancourt C, Raynaud N, Dhorne-Pollet S, Pollet N, Bernard O, Hadchouel M, Meunier-Rotival M. Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome. Gastroenterology. 1999 May;116(5):1141-8. PMID:10220506
  5. ↑ Pilia G, Uda M, Macis D, Frau F, Crisponi L, Balli F, Barbera C, Colombo C, Frediani T, Gatti R, Iorio R, Marazzi MG, Marcellini M, Musumeci S, Nebbia G, Vajro P, Ruffa G, Zancan L, Cao A, DeVirgilis S. Jagged-1 mutation analysis in Italian Alagille syndrome patients. Hum Mutat. 1999;14(5):394-400. PMID:10533065 doi:<394::AID-HUMU5>3.0.CO;2-1 10.1002/(SICI)1098-1004(199911)14:5<394::AID-HUMU5>3.0.CO;2-1
  6. ↑ Heritage ML, MacMillan JC, Colliton RP, Genin A, Spinner NB, Anderson GJ. Jagged1 (JAG1) mutation detection in an Australian Alagille syndrome population. Hum Mutat. 2000 Nov;16(5):408-16. PMID:11058898 doi:<408::AID-HUMU5>3.0.CO;2-9 10.1002/1098-1004(200011)16:5<408::AID-HUMU5>3.0.CO;2-9
  7. ↑ Morrissette JD, Colliton RP, Spinner NB. Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome. Hum Mol Genet. 2001 Feb 15;10(4):405-13. PMID:11157803
  8. ↑ Crosnier C, Driancourt C, Raynaud N, Hadchouel M, Meunier-Rotival M. Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome. Hum Mutat. 2001;17(1):72-3. PMID:11139247 doi:<72::AID-HUMU11>3.0.CO;2-U 10.1002/1098-1004(2001)17:1<72::AID-HUMU11>3.0.CO;2-U
  9. ↑ Colliton RP, Bason L, Lu FM, Piccoli DA, Krantz ID, Spinner NB. Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients. Hum Mutat. 2001 Feb;17(2):151-2. PMID:11180599 doi:<151::AID-HUMU8>3.0.CO;2-T 10.1002/1098-1004(200102)17:2<151::AID-HUMU8>3.0.CO;2-T
  10. ↑ Heritage ML, MacMillan JC, Anderson GJ. DHPLC mutation analysis of Jagged1 (JAG1) reveals six novel mutations in Australian alagille syndrome patients. Hum Mutat. 2002 Dec;20(6):481. PMID:12442286 doi:10.1002/humu.9095
  11. ↑ Ropke A, Kujat A, Graber M, Giannakudis J, Hansmann I. Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. Hum Mutat. 2003 Jan;21(1):100. PMID:12497640 doi:10.1002/humu.9102
  12. ↑ Jurkiewicz D, Popowska E, Glaser C, Hansmann I, Krajewska-Walasek M. Twelve novel JAG1 gene mutations in Polish Alagille syndrome patients. Hum Mutat. 2005 Mar;25(3):321. PMID:15712272 doi:10.1002/humu.9313
  13. ↑ Warthen DM, Moore EC, Kamath BM, Morrissette JJ, Sanchez-Lara PA, Piccoli DA, Krantz ID, Spinner NB. Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate. Hum Mutat. 2006 May;27(5):436-43. PMID:16575836 doi:10.1002/humu.20310
  14. ↑ Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997 Jul;16(3):235-42. PMID:9207787 doi:10.1038/ng0797-235
  15. ↑ Eldadah ZA, Hamosh A, Biery NJ, Montgomery RA, Duke M, Elkins R, Dietz HC. Familial Tetralogy of Fallot caused by mutation in the jagged1 gene. Hum Mol Genet. 2001 Jan 15;10(2):163-9. PMID:11152664
  16. ↑ Li L, Milner LA, Deng Y, Iwata M, Banta A, Graf L, Marcovina S, Friedman C, Trask BJ, Hood L, Torok-Storb B. The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. Immunity. 1998 Jan;8(1):43-55. PMID:9462510
  17. ↑ Cordle J, Johnson S, Tay JZ, Roversi P, Wilkin MB, de Madrid BH, Shimizu H, Jensen S, Whiteman P, Jin B, Redfield C, Baron M, Lea SM, Handford PA. A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition. Nat Struct Mol Biol. 2008 Aug;15(8):849-57. Epub 2008 Jul 27. PMID:18660822 doi:10.1038/nsmb.1457
  18. ↑ Chillakuri CR, Sheppard D, Ilagan MX, Holt LR, Abbott F, Liang S, Kopan R, Handford PA, Lea SM. Structural Analysis Uncovers Lipid-Binding Properties of Notch Ligands. Cell Rep. 2013 Nov 13. pii: S2211-1247(13)00613-X. doi:, 10.1016/j.celrep.2013.10.029. PMID:24239355 doi:http://dx.doi.org/10.1016/j.celrep.2013.10.029

4cc1, resolution 2.84Å

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