The classification of FAS death domain

The structure of the Fas death domain consists of six amphipathic alpha-helices arranged antiparallel to one another.

 

(FAS alias: APT1, TNFRSF6, CD95, APO-1… from Human)

FAS belongs to the tumor necrosis factor receptor superfamily as member 6. It activates cell death upon ligand binding with the complex of its extracellular domains. Signaling for cell death by Fas/APO1 occurs via a distinct region in its intracellular domain – the death domain(DD).

 

The above schematic diagram of the integrated apoptotic pathways showing some of the known components of the intrinsic and death receptor apoptotic programs (Cell, Vol. 108, 153-164, Jan. 25, 2002).

The following cartoon is copied from St. Jude Children's Research Hospital reseach program. It illustrates the pathways where the death domain of FADD binds with the Fas intracellular Death domain.

 

 

 

 FAS death domain (1ddf):

Exp. Method: NMR, Minimized Average Structure

Primary Citation: Huang, B., Eberstadt, M., Olejniczak, E. T., Meadows, R. P., Fesik, S. W.: NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Nature 384 pp. 638 (1996)
[ Medline ]

CATH classification of FAS death domain:

Homologous Superfamily 1.10.533.10

CLASS: Mainly Alpha, six amphipathic alpha-helices

ARCHITECTURE: Orthogonal Bundle, antiparallel to one another

TOPOLOGY: Death Domain, Fas;

HOMOLOGOUS SUPPERFAMILY: DEATH DOMAIN

 

 

 

Figure 3. a, Sequence alignment of the death domains of Fas and TNF-R1. The numbering in Fas is as described in [30]. Identical residues are highlighted in blue, and homologous residues in grey. The helices in the NMR structure of the Fas death domain are indicated. Mutations are indicated by an arrow pointing to the new amino acid (one-letter code). A minus sign immediately below the amino acid for TNF-R1 indicates a loss in TNF-R1-mediated cytotoxicity [5]. A minus sign above the Fas mutation indicates that this mutant aggregates less than the wild-type protein. b, Stereoview of the backbone (N, Calpha, C') of 20 superimposed NMR-derived structures of the Fas death domain. The side chains of residues in the hydrophobic core are coloured red. c d, Ribbons [28] depictions of the averaged minimized NMR structure of the Fas death domain.

 

SCOP classification of FAS death domain:

  1. Root: scop
  2. Class: All alpha proteins
  3. Fold: DEATH domain
    6 helices: closed bundle; greek-key; internal pseudo twofold symmetry
  4. Superfamily: DEATH domain
  5. Family: DEATH domain
    Caspase recruitment domain, CARD
  6. Protein: Fas
  7. Species: Human (Homo sapiens)

 

Structure Alignment - 1DDF:_ Neighbors:

1DDF:_ 9/210 SDVDLSKY----ITTIAGVMTL-SQVKGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLR
1E41:A 8/97 ----DLCA----AFNVICDNVG-KDWRRLARQLKVSDTKIDSIEDRYPRNLTERVRESLR
1D2Z:C 9/31 NTMAIRLLPLPVRAQLCAHLDALDVWQQLATAVKLYPDQVEQISSQKQRG-RSASNEFLN
1NGR:_ 2/336 --NLYSSLPLTKREEVEKLLNG-DTWRHLAGELGYQPEHIDSFTHEA-----CPVRALLA

1DDF:_ 64/265 NWHQLHGKKEAYDTLIKDLKKANLCTLAEKIQTIILKDI
1E41:A 59/148 IWKNTEKENATVAHLVGALRSCQMNLVADLVQEVQQARD
1D2Z:C 68/90 IWGGQYNH--TVQTLFALFKKLKLHNAMRLIKD------
1NGR:_ 54/388 SWGAQDSA--TLDALLAALRRIQRADIVESLCSE-----

 

 3 D Alignment: