3ezq

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of the Fas/FADD Death Domain Complex

Structural highlights

3ezq is a 16 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 2.73Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TNR6_HUMAN Defects in FAS are the cause of autoimmune lymphoproliferative syndrome type 1A (ALPS1A) [MIM:601859; also known as Canale-Smith syndrome (CSS). ALPS is a childhood syndrome involving hemolytic anemia and thrombocytopenia with massive lymphadenopathy and splenomegaly.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13]

Function

TNR6_HUMAN Receptor for TNFSF6/FASLG. 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. FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T-cells, or both. The secreted isoforms 2 to 6 block apoptosis (in vitro).^[14] ^[15]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The death inducing signalling complex (DISC) formed by Fas receptor, FADD (Fas-associated death domain protein) and caspase 8 is a pivotal trigger of apoptosis. The Fas-FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death. A highly oligomeric network of homotypic protein interactions comprised of the death domains of Fas and FADD is at the centre of DISC formation. Thus, characterizing the mechanistic basis for the Fas-FADD interaction is crucial for understanding DISC signalling but has remained unclear largely because of a lack of structural data. We have successfully formed and isolated the human Fas-FADD death domain complex and report the 2.7 A crystal structure. The complex shows a tetrameric arrangement of four FADD death domains bound to four Fas death domains. We show that an opening of the Fas death domain exposes the FADD binding site and simultaneously generates a Fas-Fas bridge. The result is a regulatory Fas-FADD complex bridge governed by weak protein-protein interactions revealing a model where the complex itself functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. In addition to depicting a previously unknown mode of death domain interactions, these results further uncover a mechanism for receptor signalling solely by oligomerization and clustering events.

The Fas-FADD death domain complex structure unravels signalling by receptor clustering.,Scott FL, Stec B, Pop C, Dobaczewska MK, Lee JJ, Monosov E, Robinson H, Salvesen GS, Schwarzenbacher R, Riedl SJ Nature. 2009 Feb 19;457(7232):1019-22. Epub 2008 Dec 31. PMID:19118384^[16]

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

References

↑ Del-Rey MJ, Manzanares J, Bosque A, Aguilo JI, Gomez-Rial J, Roldan E, Serrano A, Anel A, Paz-Artal E, Allende LM. Autoimmune lymphoproliferative syndrome (ALPS) in a patient with a new germline Fas gene mutation. Immunobiology. 2007;212(2):73-83. Epub 2007 Jan 19. PMID:17336828 doi:10.1016/j.imbio.2006.12.003
↑ Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, Strober W, Lenardo MJ, Puck JM. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995 Jun 16;81(6):935-46. PMID:7540117
↑ Drappa J, Vaishnaw AK, Sullivan KE, Chu JL, Elkon KB. Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med. 1996 Nov 28;335(22):1643-9. PMID:8929361
↑ Bettinardi A, Brugnoni D, Quiros-Roldan E, Malagoli A, La Grutta S, Correra A, Notarangelo LD. Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. Blood. 1997 Feb 1;89(3):902-9. PMID:9028321
↑ Sneller MC, Wang J, Dale JK, Strober W, Middelton LA, Choi Y, Fleisher TA, Lim MS, Jaffe ES, Puck JM, Lenardo MJ, Straus SE. Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood. 1997 Feb 15;89(4):1341-8. PMID:9028957
↑ Pensati L, Costanzo A, Ianni A, Accapezzato D, Iorio R, Natoli G, Nisini R, Almerighi C, Balsano C, Vajro P, Vegnente A, Levrero M. Fas/Apo1 mutations and autoimmune lymphoproliferative syndrome in a patient with type 2 autoimmune hepatitis. Gastroenterology. 1997 Oct;113(4):1384-9. PMID:9322534
↑ Infante AJ, Britton HA, DeNapoli T, Middelton LA, Lenardo MJ, Jackson CE, Wang J, Fleisher T, Straus SE, Puck JM. The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis. J Pediatr. 1998 Nov;133(5):629-33. PMID:9821419
↑ Jackson CE, Fischer RE, Hsu AP, Anderson SM, Choi Y, Wang J, Dale JK, Fleisher TA, Middelton LA, Sneller MC, Lenardo MJ, Straus SE, Puck JM. Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. Am J Hum Genet. 1999 Apr;64(4):1002-14. PMID:10090885
↑ Rieux-Laucat F, Blachere S, Danielan S, De Villartay JP, Oleastro M, Solary E, Bader-Meunier B, Arkwright P, Pondare C, Bernaudin F, Chapel H, Nielsen S, Berrah M, Fischer A, Le Deist F. Lymphoproliferative syndrome with autoimmunity: A possible genetic basis for dominant expression of the clinical manifestations. Blood. 1999 Oct 15;94(8):2575-82. PMID:10515860
↑ Peters AM, Kohfink B, Martin H, Griesinger F, Wormann B, Gahr M, Roesler J. Defective apoptosis due to a point mutation in the death domain of CD95 associated with autoimmune lymphoproliferative syndrome, T-cell lymphoma, and Hodgkin's disease. Exp Hematol. 1999 May;27(5):868-74. PMID:10340403
↑ Vaishnaw AK, Orlinick JR, Chu JL, Krammer PH, Chao MV, Elkon KB. The molecular basis for apoptotic defects in patients with CD95 (Fas/Apo-1) mutations. J Clin Invest. 1999 Feb;103(3):355-63. PMID:9927496 doi:10.1172/JCI5121
↑ Straus SE, Jaffe ES, Puck JM, Dale JK, Elkon KB, Rosen-Wolff A, Peters AM, Sneller MC, Hallahan CW, Wang J, Fischer RE, Jackson CM, Lin AY, Baumler C, Siegert E, Marx A, Vaishnaw AK, Grodzicky T, Fleisher TA, Lenardo MJ. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood. 2001 Jul 1;98(1):194-200. PMID:11418480
↑ Wang L, Yang JK, Kabaleeswaran V, Rice AJ, Cruz AC, Park AY, Yin Q, Damko E, Jang SB, Raunser S, Robinson CV, Siegel RM, Walz T, Wu H. The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Mol Biol. 2010 Nov;17(11):1324-9. Epub 2010 Oct 10. PMID:20935634 doi:10.1038/nsmb.1920
↑ Cascino I, Fiucci G, Papoff G, Ruberti G. Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing. J Immunol. 1995 Mar 15;154(6):2706-13. PMID:7533181
↑ Scott FL, Stec B, Pop C, Dobaczewska MK, Lee JJ, Monosov E, Robinson H, Salvesen GS, Schwarzenbacher R, Riedl SJ. The Fas-FADD death domain complex structure unravels signalling by receptor clustering. Nature. 2009 Feb 19;457(7232):1019-22. Epub 2008 Dec 31. PMID:19118384 doi:nature07606
↑ Scott FL, Stec B, Pop C, Dobaczewska MK, Lee JJ, Monosov E, Robinson H, Salvesen GS, Schwarzenbacher R, Riedl SJ. The Fas-FADD death domain complex structure unravels signalling by receptor clustering. Nature. 2009 Feb 19;457(7232):1019-22. Epub 2008 Dec 31. PMID:19118384 doi:nature07606

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3ezq"

@@ Line 3: / Line 3: @@
 <StructureSection load='3ezq' size='340' side='right'caption='[[3ezq]], [[Resolution|resolution]] 2.73&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3ezq]] is a 16 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EZQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3EZQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3ezq]] is a 16 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=3EZQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3EZQ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.73&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FAS, APT1, FAS1, TNFRSF6 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), FADD, MORT1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=3ezq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ezq OCA], [https://pdbe.org/3ezq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ezq RCSB], [https://www.ebi.ac.uk/pdbsum/3ezq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ezq ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/TNR6_HUMAN TNR6_HUMAN]] Defects in FAS are the cause of autoimmune lymphoproliferative syndrome type 1A (ALPS1A) [MIM:[https://omim.org/entry/601859 601859]]; also known as Canale-Smith syndrome (CSS). ALPS is a childhood syndrome involving hemolytic anemia and thrombocytopenia with massive lymphadenopathy and splenomegaly.<ref>PMID:17336828</ref> <ref>PMID:7540117</ref> <ref>PMID:8929361</ref> <ref>PMID:9028321</ref> <ref>PMID:9028957</ref> <ref>PMID:9322534</ref> <ref>PMID:9821419</ref> <ref>PMID:10090885</ref> <ref>PMID:10515860</ref> <ref>PMID:10340403</ref> <ref>PMID:9927496</ref> <ref>PMID:11418480</ref> <ref>PMID:20935634</ref>  [[https://www.uniprot.org/uniprot/FADD_HUMAN FADD_HUMAN]] Defects in FADD are the cause of infections recurrent associated with encephalopathy hepatic dysfunction and cardiovascular malformations (IEHDCM) [MIM:[https://omim.org/entry/613759 613759]]. A condition with biological features of autoimmune lymphoproliferative syndrome such as high-circulating CD4(-)CD8(-)TCR-alpha-beta(+) T-cell counts, and elevated IL10 and FASL levels. Affected individuals suffer from recurrent, stereotypical episodes of fever, encephalopathy, and mild liver dysfunction sometimes accompanied by generalized seizures. The episodes can be triggered by varicella zoster virus (VZV), measles mumps rubella (MMR) attenuated vaccine, parainfluenza virus, and Epstein-Barr virus (EBV).<ref>PMID:21109225</ref>
+[https://www.uniprot.org/uniprot/TNR6_HUMAN TNR6_HUMAN] Defects in FAS are the cause of autoimmune lymphoproliferative syndrome type 1A (ALPS1A) [MIM:[https://omim.org/entry/601859 601859]; also known as Canale-Smith syndrome (CSS). ALPS is a childhood syndrome involving hemolytic anemia and thrombocytopenia with massive lymphadenopathy and splenomegaly.<ref>PMID:17336828</ref> <ref>PMID:7540117</ref> <ref>PMID:8929361</ref> <ref>PMID:9028321</ref> <ref>PMID:9028957</ref> <ref>PMID:9322534</ref> <ref>PMID:9821419</ref> <ref>PMID:10090885</ref> <ref>PMID:10515860</ref> <ref>PMID:10340403</ref> <ref>PMID:9927496</ref> <ref>PMID:11418480</ref> <ref>PMID:20935634</ref>
 == Function ==
-[[https://www.uniprot.org/uniprot/TNR6_HUMAN TNR6_HUMAN]] Receptor for TNFSF6/FASLG. 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. FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T-cells, or both. The secreted isoforms 2 to 6 block apoptosis (in vitro).<ref>PMID:7533181</ref> <ref>PMID:19118384</ref>  [[https://www.uniprot.org/uniprot/FADD_HUMAN FADD_HUMAN]] Apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. The resulting aggregate called the death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation. Active caspase-8 initiates the subsequent cascade of caspases mediating apoptosis. Involved in interferon-mediated antiviral immune response, playing a role in the positive regulation of interferon signaling.<ref>PMID:21109225</ref> <ref>PMID:16762833</ref> <ref>PMID:19118384</ref> <ref>PMID:20935634</ref>
+[https://www.uniprot.org/uniprot/TNR6_HUMAN TNR6_HUMAN] Receptor for TNFSF6/FASLG. 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. FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T-cells, or both. The secreted isoforms 2 to 6 block apoptosis (in vitro).<ref>PMID:7533181</ref> <ref>PMID:19118384</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 38: / Line 38: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Riedl, S J]]
+[[Category: Riedl SJ]]
-[[Category: Robinson, H]]
+[[Category: Robinson H]]
-[[Category: Schwarzenbacher, R]]
+[[Category: Schwarzenbacher R]]
-[[Category: Stec, B]]
+[[Category: Stec B]]
-[[Category: Apoptosis]]
-[[Category: Disc]]
-[[Category: Fa]]
-[[Category: Fadd]]
-[[Category: Membrane]]
-[[Category: Receptor]]
-[[Category: Transmembrane]]

3ezq

From Proteopedia

Current revision

Crystal Structure of the Fas/FADD Death Domain Complex

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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