2na7

Structural highlights

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]}

References

1. ↑ 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
2. ↑ 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
3. ↑ 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
4. ↑ 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
5. ↑ 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
6. ↑ 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
7. ↑ 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
8. ↑ 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
9. ↑ 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
10. ↑ 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
11. ↑ 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
12. ↑ 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
13. ↑ 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
14. ↑ 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
15. ↑ 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
16. ↑ Fu Q, Fu TM, Cruz AC, Sengupta P, Thomas SK, Wang S, Siegel RM, Wu H, Chou JJ. Structural Basis and Functional Role of Intramembrane Trimerization of the Fas/CD95 Death Receptor. Mol Cell. 2016 Feb 18;61(4):602-13. doi: 10.1016/j.molcel.2016.01.009. Epub 2016 , Feb 4. PMID:26853147 doi:http://dx.doi.org/10.1016/j.molcel.2016.01.009