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PR01236

Identifier
TNFBETA  [View Relations]  [View Alignment]  
Accession
PR01236
No. of Motifs
7
Creation Date
20-OCT-1999
Title
Tumour necrosis factor beta (lymphotoxin-alpha) signature
Database References
PRINTS; PR01234 TNECROSISFCT
INTERPRO; IPR002960
PDB; 1TNR
SCOP; 1TNR
CATH; 1TNR
Literature References
1. FRANSEN, L., MULLER, R., MARMENOUT, A., TAVERNIER, J., VAN DER
HEYDEN, J., KAWASHIMA, E., CHOLLET, A., TIZARD, R., VAN HEUVERSWYN, H.
AND VAN VLIET, A.
Molecular cloning of mouse tumour necrosis factor cDNA and its eukaryotic
expression.
NUCLEIC ACIDS RES. 13 4417-4429 (1985).
 
2. KRIEGLER, M., PEREZ, C., DEFAY, K., ALBERT, I. AND LU, S.D. 
A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane
protein: ramifications for the complex physiology of TNF.
CELL 53 45-53 (1988). 
 
3. SHERRY, B., JUE, D.M., ZENTELLA, A. AND CERAMI, A.
Characterization of high molecular weight glycosylated forms of murine 
tumor necrosis factor.
BIOCHEM.BIOPHYS.RES.COMMUN. 173 1072-1078 (1990). 
 
4. CSEH, K. AND BEUTLER, B.
Alternative cleavage of the cachectin/tumor necrosis factor propeptide 
results in a larger, inactive form of secreted protein.
J.BIOL.CHEM. 264 16256-16260 (1989). 
 
5. ECK, M.J., ULTSCH, M., RINDERKNECHT, E., DE VOS, A.M. AND SPRANG, S.R.
The structure of human lymphotoxin (tumor necrosis factor-beta) at 1.9A
resolution.
J.BIOL.CHEM. 267 2119-2122 (1992).

Documentation
Tumor necrosis factor (TNF) (or cachectin) is a monocyte-derived cytotoxin
that has been implicated in tumour regression, septic shock and cachexia
[1,2]. The protein is synthesised as a prohormone with an unusually long 
and atypical signal sequence, which is absent from the mature secreted
cytokine [3]. A short hydrophobic stretch of amino acids serves to anchor 
the prohormone in lipid bilayers [4]. Both the mature protein and a 
partially-processed form of the hormone are secreted after cleavage of the
propeptide [4]. 
 
Lymphotoxin-alpha (LT-alpha or TNF-beta) and lymphotoxin-beta (LT-beta) are
related cytokines produced by lymphocytes. The proteins are cytotoxic for a
wide range of tumour cells in vitro and in vivo.
 
The structure of TNF-beta has been determined to 1.9A using X-ray 
crystallography and phase determination via molecular replacement using 
TNF-alpha [5]. Like TNF-alpha, lymphotoxin folds to form a `jellyroll' beta-
sheet sandwich. Three-fold related LT subunits form a trimer primarily
stabilised by hydrophobic interactions [5]. A cluster of 6 basic residues 
around the 3-fold axis is thought to account for the acid lability of the
trimer. Although the structural cores of TNF-alpha and LT are similar,
insertions and deletions relative to TNF-alpha occur in loops at the "top"
of the LT trimer, significantly altering the local structure [5]. The
sites of two mutations (Asp-50 and Tyr-108) that abolish the cytotoxicity 
of LT are contained within poorly-ordered loops that flank the cleft between
neighboring subunits at the base of the molecule, suggesting that the
receptor recognises an intersubunit binding site [5].
 
TNFBETA is a 7-element fingerprint that provides a signature for tumour 
necrosis factor beta. The fingerprint was derived from an initial
alignment of 6 sequences: the motifs were drawn from conserved regions
spanning virtually the full alignment length, focusing on those sections
that characterise TNF-beta but distinguish it from the rest of the TNF
family - motifs 1-2 were drawn from the N-terminus; motif 3 encodes beta-
strands 2 and 3; motif 4 spans strands 4, 5 and the N-terminus of strand 6;
motif 5 encodes helix 1 and strand 7; motif 6 spans strand 8 and the 
N-terminus of strand 9; and motif 7 spans strand 10 and helix 2. A single
iteration on SPTR37_10f was required to reach convergence, no further 
sequences being identified beyond the starting set.
Summary Information
6 codes involving  7 elements
0 codes involving 6 elements
0 codes involving 5 elements
0 codes involving 4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
76666666
60000000
50000000
40000000
30000000
20000000
1234567
True Positives
TNFB_BOVIN    TNFB_HUMAN    TNFB_MOUSE    TNFB_PIG      
TNFB_RABIT TNFB_RAT
Sequence Titles
TNFB_BOVIN  LYMPHOTOXIN-ALPHA PRECURSOR (LT-ALPHA) (TNF-BETA) - BOS TAURUS (BOVINE). 
TNFB_HUMAN LYMPHOTOXIN-ALPHA PRECURSOR (LT-ALPHA) (TNF-BETA) - HOMO SAPIENS (HUMAN).
TNFB_MOUSE LYMPHOTOXIN-ALPHA PRECURSOR (LT-ALPHA) (TNF-BETA) - MUS MUSCULUS (MOUSE).
TNFB_PIG LYMPHOTOXIN-ALPHA PRECURSOR (LT-ALPHA) (TNF-BETA) - SUS SCROFA (PIG).
TNFB_RABIT LYMPHOTOXIN-ALPHA PRECURSOR (LT-ALPHA) (TNF-BETA) - ORYCTOLAGUS CUNICULUS (RABBI
TNFB_RAT LYMPHOTOXIN-ALPHA PRECURSOR (LT-ALPHA) (TNF-BETA) - RATTUS NORVEGICUS (RAT).
Scan History
SPTR37_10f 1  100  NSINGLE    
Initial Motifs
Motif 1  width=17
Element Seqn Id St Int Rpt
LLGLLLALPPEAQGLPG TNFB_PIG 20 20 -
LLGLLLALPLGAQGLSG TNFB_MOUSE 20 20 -
LLGLLLALPLGAQGLSG TNFB_RAT 20 20 -
LLGLLLALPLEAQGLRG TNFB_BOVIN 20 20 -
LGLLLAPPPPGAQGLPG TNFB_RABIT 13 13 -
LLGLLLVLLPGAQGLPG TNFB_HUMAN 21 21 -

Motif 2 width=19
Element Seqn Id St Int Rpt
SAAQPAHQHPPKHLARGTL TNFB_PIG 42 5 -
SAARTAHPLPQKHLTHGIL TNFB_MOUSE 40 3 -
SASRTAHQPPQKHLTHGLL TNFB_RAT 40 3 -
SAAQPAHQQLPTPFTRGTL TNFB_BOVIN 42 5 -
SAARNAQQRLQKHFGHSTL TNFB_RABIT 35 5 -
SAAQTARQHPKMHLAHSTL TNFB_HUMAN 43 5 -

Motif 3 width=18
Element Seqn Id St Int Rpt
PSTPDSLRWRANTDRAFL TNFB_PIG 70 9 -
PSKQNSLLWRASTDRAFL TNFB_MOUSE 68 9 -
PSKQNSLLWRANTDRAFL TNFB_RAT 68 9 -
PSTQDSLRWRANTDRAFL TNFB_BOVIN 70 9 -
PSAQDSLRWRANTDRAFL TNFB_RABIT 63 9 -
PSKQNSLLWRANTDRAFL TNFB_HUMAN 71 9 -

Motif 4 width=19
Element Seqn Id St Int Rpt
GFLLSNNSLLVPTSGLYFV TNFB_PIG 90 2 -
GFSLSNNSLLIPTSGLYFV TNFB_MOUSE 88 2 -
GFSLNNNSLLIPTSGLYFV TNFB_RAT 88 2 -
GFSLSNNSLLVPTSGLYFV TNFB_BOVIN 90 2 -
GFSLSNNSLLVPSSGLYFV TNFB_RABIT 83 2 -
GFSLSNNSLLVPTSGIYFV TNFB_HUMAN 91 2 -

Motif 5 width=21
Element Seqn Id St Int Rpt
PKATPTPLYLAHEVQLFSSQY TNFB_PIG 121 12 -
PRAIPTPIYLAHEVQLFSSQY TNFB_MOUSE 119 12 -
PRAIPTPIYLAHEVQLFSSQY TNFB_RAT 119 12 -
PRATPTPLYLAHEVQLFSPQY TNFB_BOVIN 121 12 -
PKAVPTPLYLAHEVQLFSSQY TNFB_RABIT 114 12 -
PKATSSPLYLAHEVQLFSSQY TNFB_HUMAN 122 12 -

Motif 6 width=20
Element Seqn Id St Int Rpt
PLLSAQKSVCPGPQGPWVRS TNFB_PIG 146 4 -
PLLSAQKSVYPGLQGPWVRS TNFB_MOUSE 144 4 -
PLLSAQKSVYPGLQGPWVRS TNFB_RAT 144 4 -
PLLSAQKSVCPGPQGPWVRS TNFB_BOVIN 146 4 -
PLLSAQKSVCPGPQGPWVRS TNFB_RABIT 139 4 -
PLLSSQKMVYPGLQEPWLHS TNFB_HUMAN 147 4 -

Motif 7 width=18
Element Seqn Id St Int Rpt
QLSTHTDGTPHLLLSPSS TNFB_PIG 179 13 -
QLSTHTDGISHLHFSPSS TNFB_MOUSE 177 13 -
QLSTHTDGISHLHFSPST TNFB_RAT 177 13 -
QLSTHTDGISHLLLSPSS TNFB_BOVIN 179 13 -
QLSTHTDGIAHLLLSPSS TNFB_RABIT 172 13 -
QLSTHTDGIPHLVLSPST TNFB_HUMAN 180 13 -
Final Motifs
Motif 1  width=17
Element Seqn Id St Int Rpt
LLGLLLALPPEAQGLPG TNFB_PIG 20 20 -
LLGLLLALPLGAQGLSG TNFB_MOUSE 20 20 -
LLGLLLALPLGAQGLSG TNFB_RAT 20 20 -
LLGLLLALPLEAQGLRG TNFB_BOVIN 20 20 -
LGLLLAPPPPGAQGLPG TNFB_RABIT 13 13 -
LLGLLLVLLPGAQGLPG TNFB_HUMAN 21 21 -

Motif 2 width=19
Element Seqn Id St Int Rpt
SAAQPAHQHPPKHLARGTL TNFB_PIG 42 5 -
SAARTAHPLPQKHLTHGIL TNFB_MOUSE 40 3 -
SASRTAHQPPQKHLTHGLL TNFB_RAT 40 3 -
SAAQPAHQQLPTPFTRGTL TNFB_BOVIN 42 5 -
SAARNAQQRLQKHFGHSTL TNFB_RABIT 35 5 -
SAAQTARQHPKMHLAHSTL TNFB_HUMAN 43 5 -

Motif 3 width=18
Element Seqn Id St Int Rpt
PSTPDSLRWRANTDRAFL TNFB_PIG 70 9 -
PSKQNSLLWRASTDRAFL TNFB_MOUSE 68 9 -
PSKQNSLLWRANTDRAFL TNFB_RAT 68 9 -
PSTQDSLRWRANTDRAFL TNFB_BOVIN 70 9 -
PSAQDSLRWRANTDRAFL TNFB_RABIT 63 9 -
PSKQNSLLWRANTDRAFL TNFB_HUMAN 71 9 -

Motif 4 width=19
Element Seqn Id St Int Rpt
GFLLSNNSLLVPTSGLYFV TNFB_PIG 90 2 -
GFSLSNNSLLIPTSGLYFV TNFB_MOUSE 88 2 -
GFSLNNNSLLIPTSGLYFV TNFB_RAT 88 2 -
GFSLSNNSLLVPTSGLYFV TNFB_BOVIN 90 2 -
GFSLSNNSLLVPSSGLYFV TNFB_RABIT 83 2 -
GFSLSNNSLLVPTSGIYFV TNFB_HUMAN 91 2 -

Motif 5 width=21
Element Seqn Id St Int Rpt
PKATPTPLYLAHEVQLFSSQY TNFB_PIG 121 12 -
PRAIPTPIYLAHEVQLFSSQY TNFB_MOUSE 119 12 -
PRAIPTPIYLAHEVQLFSSQY TNFB_RAT 119 12 -
PRATPTPLYLAHEVQLFSPQY TNFB_BOVIN 121 12 -
PKAVPTPLYLAHEVQLFSSQY TNFB_RABIT 114 12 -
PKATSSPLYLAHEVQLFSSQY TNFB_HUMAN 122 12 -

Motif 6 width=20
Element Seqn Id St Int Rpt
PLLSAQKSVCPGPQGPWVRS TNFB_PIG 146 4 -
PLLSAQKSVYPGLQGPWVRS TNFB_MOUSE 144 4 -
PLLSAQKSVYPGLQGPWVRS TNFB_RAT 144 4 -
PLLSAQKSVCPGPQGPWVRS TNFB_BOVIN 146 4 -
PLLSAQKSVCPGPQGPWVRS TNFB_RABIT 139 4 -
PLLSSQKMVYPGLQEPWLHS TNFB_HUMAN 147 4 -

Motif 7 width=18
Element Seqn Id St Int Rpt
QLSTHTDGTPHLLLSPSS TNFB_PIG 179 13 -
QLSTHTDGISHLHFSPSS TNFB_MOUSE 177 13 -
QLSTHTDGISHLHFSPST TNFB_RAT 177 13 -
QLSTHTDGISHLLLSPSS TNFB_BOVIN 179 13 -
QLSTHTDGIAHLLLSPSS TNFB_RABIT 172 13 -
QLSTHTDGIPHLVLSPST TNFB_HUMAN 180 13 -