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Reviewed, UniProtKB/Swiss-Prot O15519 (CFLAR_HUMAN)

Last modified December 16, 2008. Version 90. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein namesRecommended name:
    CASP8 and FADD-like apoptosis regulator
Alternative name(s):
    Cellular FLICE-like inhibitory protein
      Short name=c-FLIP
    Caspase-eight-related protein
      Short name=Casper
    Caspase-like apoptosis regulatory protein
      Short name=CLARP
    MACH-related inducer of toxicity
      Short name=MRIT
    Caspase homolog
      Short name=CASH
    Inhibitor of FLICE
      Short name=I-FLICE
    FADD-like antiapoptotic molecule 1
      Short name=FLAME-1
    Usurpin
Cleaved into the following 2 chains:
    1- Recommended name:
            CASP8 and FADD-like apoptosis regulator subunit p43
    2- Recommended name:
            CASP8 and FADD-like apoptosis regulator subunit p12
Gene names
Name: CFLAR
Synonyms: CASH, CASP8AP1, CLARP, MRIT
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length480 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level.

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General annotation (Comments)

Function

Apoptosis regulator protein which may function as a crucial link between cell survival and cell death pathways in mammalian cells. Acts as an inhibitor of TNFRSF6 mediated apoptosis. A proteolytic fragment (p43) is likely retained in the death-inducing signaling complex (DISC) thereby blocking further recruitment and processing of caspase-8 at the complex. Full length and shorter isoforms have been shown either to induce apoptosis or to reduce TNFRSF-triggered apoptosis. Lacks enzymatic (caspase) activity. Ref.14

Subunit structure

TNFRSF6 stimulation triggers recruitment to the death-inducing signaling complex (DISC) formed by TNFRSF6, FADD and caspase-8. A proteolytic fragment (p43) stays associated with the DISC. Also interacts with caspase-10, caspase-3, TRAF1, TRAF2 and Bcl-X(L) (in vitro). Interacts with HBV protein X. Ref.7

Tissue specificity

Widely expressed. Higher expression in skeletal muscle, pancreas, heart, kidney, placenta, and peripheral blood leukocytes. Also detected in diverse cell lines. Isoform 8 is predominantly expressed in testis and skeletal muscle.

Induction

Repressed by IL-2 after TCR stimulation, during progression to the S-phase of the cell cycle. Ref.15

Domain

The caspase domain lacks the active sites residues involved in catalysis.

Post-translational modification

Proteolytically processed; probably by caspase-8. Processing likely occurs at the DISC and generates subunit p43 and p12.

Sequence similarities

Belongs to the peptidase C14A family.

Contains 2 DED (death effector) domains.

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Binary interactions

With

Entry

#Exp.

IntAct

Notes

DOK2O604961EBI-514941,EBI-1046024
SF3B3Q153931EBI-514941,EBI-346977

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Alternative products

This entry describes 14 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O15519-1)

Also known as: FLIP-L; CLARP1; MRIT alpha-1; CASH alpha; I-FLICE 1; FLAME-1 gamma; Usurpin alpha;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: O15519-2)

Also known as: FLIP-S; CLARP2; MRIT beta-1; CASH beta;

The sequence of this isoform differs from the canonical sequence as follows:
     203-221: LHNGRSKEQRLKEQLGAQQ → MITPYAHCPDLKILGNCSM
     222-480: Missing.
Isoform 3 (identifier: O15519-3)

Also known as: MRIT alpha-2;

The sequence of this isoform differs from the canonical sequence as follows:
     1-96: Missing.
     436-480: KRPLLDLHIELNGYMYDWNSRVSAKEKYYVWLQHTLRKKLILSYT → GTIPGSGITESKDMHFSSLGCILLDVL
Isoform 4 (identifier: O15519-4)

Also known as: I-FLICE 2;

The sequence of this isoform differs from the canonical sequence as follows:
     1-245: Missing.
Isoform 5 (identifier: O15519-5)

Also known as: I-FLICE 3;

The sequence of this isoform differs from the canonical sequence as follows:
     449-480: YMYDWNSRVSAKEKYYVWLQHTLRKKLILSYT → L
Isoform 6 (identifier: O15519-6)

Also known as: I-FLICE 4;

The sequence of this isoform differs from the canonical sequence as follows:
     2-30: SAEVIHQVEEALDTDEKEMLLFLCRDVAI → LERPPVCSKV
     453-480: WNSRVSAKEKYYVWLQHTLRKKLILSYT → SLEHTGGRY
Isoform 7 (identifier: O15519-7)

Also known as: I-FLICE 5;

The sequence of this isoform differs from the canonical sequence as follows:
     1-96: Missing.
     203-221: LHNGRSKEQRLKEQLGAQQ → E
     436-480: KRPLLDLHIELNGYMYDWNSRVSAKEKYYVWLQHTLRKKLILSYT → GTIPGSGITESKDMHFSSLGCILLDVL
Isoform 8 (identifier: O15519-8)

Also known as: FLAME-1 alpha;

The sequence of this isoform differs from the canonical sequence as follows:
     203-237: Missing.
Isoform 9 (identifier: O15519-9)

Also known as: FLAME-1 beta;

The sequence of this isoform differs from the canonical sequence as follows:
     203-237: Missing.
     267-305: LRDTFTSLGY...FACMPEHRDY → CGVRGPAGGQ...ARAVHSSPRS
     306-480: Missing.
Notes: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Isoform 10 (identifier: O15519-10)

Also known as: FLAME-1 delta;

The sequence of this isoform differs from the canonical sequence as follows:
     266-300: LLRDTFTSLGYEVQKFLHLSMHGISQILGQFACMP → NAHSWIFTLNSMATCMIGTAEFLPRRNIMFGCSTL
     301-480: Missing.
Isoform 11 (identifier: O15519-11)

Also known as: Usurpin beta;

The sequence of this isoform differs from the canonical sequence as follows:
     436-480: KRPLLDLHIELNGYMYDWNSRVSAKEKYYVWLQHTLRKKLILSYT → GTIPGSGITESKDMHFSSLGCILLDVL
Isoform 12 (identifier: O15519-12)

Also known as: Usurpin gamma;

The sequence of this isoform differs from the canonical sequence as follows:
     265-292: ELLRDTFTSLGYEVQKFLHLSMHGISQI → GWSAMAQSQLTAISTSQVQAILLPQPPE
     293-480: Missing.
Isoform 13 (identifier: O15519-13)

The sequence of this isoform differs from the canonical sequence as follows:
     203-480: Missing.
Isoform 14 (identifier: O15519-14)

The sequence of this isoform differs from the canonical sequence as follows:
     436-480: Missing.

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Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 376376CASP8 and FADD-like apoptosis regulator subunit p43
PRO_0000004678
Chain377 – 480104CASP8 and FADD-like apoptosis regulator subunit p12 Potential
PRO_0000004679

Regions

Domain1 – 7373DED 1
Domain92 – 17079DED 2
Region1 – 435435Not proteolytically processed and involved in apoptosis inhibition
Region1 – 305305Interaction with caspase-8 propeptide
Region1 – 227227Interaction with FADD
Region1 – 195195Interaction with caspase-8
Region192 – 480289Interaction with TRAF1 and TRAF2
Region192 – 435244Interaction with caspase-3
Region217 – 480264Interaction with caspase-8 subunits p18 and p10
Region263 – 35896Caspase
Region370 – 480111Interaction with caspase-8

Natural variations

Alternative sequence1 – 245245Missing in isoform 4.
VSP_000825
Alternative sequence1 – 9696Missing in isoform 7 and isoform 3.
VSP_000824
Alternative sequence2 – 3029SAEVI…RDVAI → LERPPVCSKV in isoform 6.
VSP_000826
Alternative sequence203 – 480278Missing in isoform 13.
VSP_000831
Alternative sequence203 – 23735Missing in isoform 8 and isoform 9.
VSP_000830
Alternative sequence203 – 22119LHNGR…LGAQQ → MITPYAHCPDLKILGNCSM in isoform 2.
VSP_000828
Alternative sequence203 – 22119LHNGR…LGAQQ → E in isoform 7.
VSP_000827
Alternative sequence222 – 480259Missing in isoform 2.
VSP_000829
Alternative sequence265 – 29228ELLRD…GISQI → GWSAMAQSQLTAISTSQVQA ILLPQPPE in isoform 12.
VSP_000832
Alternative sequence266 – 30035LLRDT…FACMP → NAHSWIFTLNSMATCMIGTA EFLPRRNIMFGCSTL in isoform 10.
VSP_000834
Alternative sequence267 – 30539LRDTF…EHRDY → CGVRGPAGGQQPLGGGWASD EECGIQGSEARAVHSSPRS in isoform 9.
VSP_000836
Alternative sequence293 – 480188Missing in isoform 12.
VSP_000833
Alternative sequence301 – 480180Missing in isoform 10.
VSP_000835
Alternative sequence306 – 480175Missing in isoform 9.
VSP_000837
Alternative sequence436 – 48045KRPLL…ILSYT → GTIPGSGITESKDMHFSSLG CILLDVL in isoform 11, isoform 7 and isoform 3.
VSP_000838
Alternative sequence436 – 48045Missing in isoform 14.
VSP_000839
Alternative sequence449 – 48032YMYDW…ILSYT → L in isoform 5.
VSP_000840
Alternative sequence453 – 48028WNSRV…ILSYT → SLEHTGGRY in isoform 6.
VSP_000841
Natural variant2031L → I: dbSNP rs13424615.
VAR_048619

Experimental info

Mutagenesis3601Y → F: Decreases apoptosis-inducing activity. Reduces interaction with caspase-3 and proteolytic processing Ref.1
Mutagenesis3761D → N or A: Abolishes proteolytic processing Ref.4
Sequence conflict130 – 1323SFL → ISW in AAC15826 and AAC15825. Ref.9
Sequence conflict3431D → E in AAC15825. Ref.9
Sequence conflict3641E → D in AAB99794. Ref.6
Sequence conflict366 – 3683QLE → PAG in AAC15825. Ref.9
Sequence conflict3691D → N in CAA74366. Ref.8
Sequence conflict3721L → F in AAB99793. Ref.6
Sequence conflict373 – 3742LE → WR in AAC15825. Ref.9

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Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (FLIP-L) (CLARP1) (MRIT alpha-1) (CASH alpha) (I-FLICE 1) (FLAME-1 gamma) (Usurpin alpha) [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: 8C6D7E92AE1EB672

FASTA48055,344
        10         20         30         40         50         60 
MSAEVIHQVE EALDTDEKEM LLFLCRDVAI DVVPPNVRDL LDILRERGKL SVGDLAELLY 

        70         80         90        100        110        120 
RVRRFDLLKR ILKMDRKAVE THLLRNPHLV SDYRVLMAEI GEDLDKSDVS SLIFLMKDYM 

       130        140        150        160        170        180 
GRGKISKEKS FLDLVVELEK LNLVAPDQLD LLEKCLKNIH RIDLKTKIQK YKQSVQGAGT 

       190        200        210        220        230        240 
SYRNVLQAAI QKSLKDPSNN FRLHNGRSKE QRLKEQLGAQ QEPVKKSIQE SEAFLPQSIP 

       250        260        270        280        290        300 
EERYKMKSKP LGICLIIDCI GNETELLRDT FTSLGYEVQK FLHLSMHGIS QILGQFACMP 

       310        320        330        340        350        360 
EHRDYDSFVC VLVSRGGSQS VYGVDQTHSG LPLHHIRRMF MGDSCPYLAG KPKMFFIQNY 

       370        380        390        400        410        420 
VVSEGQLEDS SLLEVDGPAM KNVEFKAQKR GLCTVHREAD FFWSLCTADM SLLEQSHSSP 

       430        440        450        460        470        480 
SLYLQCLSQK LRQERKRPLL DLHIELNGYM YDWNSRVSAK EKYYVWLQHT LRKKLILSYT

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Isoform 2 (FLIP-S) (CLARP2) (MRIT beta-1) (CASH beta).

Checksum: 12774D7AB3E53263
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22125,379
Isoform 3 (MRIT alpha-2).

Checksum: B5DB6C8A18608582
Show »

36641,319
Isoform 4 (I-FLICE 2).

Checksum: 1B34FA73556DC390
Show »

23527,055
Isoform 5 (I-FLICE 3).

Checksum: 8AC8D85BA2F72F7E
Show »

44951,390
Isoform 6 (I-FLICE 4).

Checksum: B20A318B728B2543
Show »

44250,661
Isoform 7 (I-FLICE 5).

Checksum: E9F524387399F9CA
Show »

34839,245
Isoform 8 (FLAME-1 alpha).

Checksum: 91CD549119606DB2
Show »

44551,330
Isoform 9 (FLAME-1 beta).

Checksum: 230E9C0C0ADD1003
Show »

27030,399
Isoform 10 (FLAME-1 delta).

Checksum: F6A777C2BA1469EF
Show »

30034,384
Isoform 11 (Usurpin beta).

Checksum: D4E0109CBA47EAA3
Show »

46252,551
Isoform 12 (Usurpin gamma).

Checksum: 542E30BD5169F336
Show »

29233,273