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PR01000

Identifier
SREBPS2PTASE  [View Relations]  [View Alignment]  
Accession
PR01000
No. of Motifs
4
Creation Date
23-DEC-1998  (UPDATE 18-JUN-1999)
Title
Sterol regulatory element binding protein site 2 protease (M50) signature
Database References

PROSITE; PS00142 ZINC_PROTEASE
BLOCKS; BL00142
PFAM; PF00099 zn-protease
INTERPRO; IPR001193
Literature References
1. RAWLINGS, N.D. AND BARRETT, A.J.
Evolutionary families of metallopeptidases.
METHODS ENZYMOL. 248 183-228 (1995).
 
2. RAWLINGS, N.D. AND BARRETT, A.J.
MEROPS - Peptidase Database
http://www.bi.bbsrc.ac.uk/merops/merops.htm
 
3. RAWLINGS, N.D. AND BARRETT, A.J.
Family M50 - S2P protease and other peptidases
http://www.bi.bbsrc.ac.uk/merops/famcards/m50.htm
 
6. RAWSON, R.B., ZELENSKI, N.G., NIJHAWAN, D., YE, J., SAKAI, Y.J.,
HASAN, M.T, CHANG, T.Y., BROWN, M.S. AND GOLDSTEIN, J.L.
Complementation cloning of S2P, a gene encoding a putative metalloprotease
required for intramembrane cleavage of SREBPs.
MOL.CELL. 1(1) 47-57 (1997).
 
5. DUNCAN, E.A., BROWN, M.S., GOLDSTEIN, J.L. AND SAKAI, J.
Cleavage site for sterol-regulated protease localized to a leu-Ser bond in
the lumenal loop of sterol regulatory element-binding protein-2.
J.BIOL.CHEM. 272(19) 12778-12785 (1997).

Documentation
Metalloproteases are the most diverse of the four main types of protease,
with more than 30 families identified to date [1]. Of these, around
half contain the HEXXH motif, which has been shown in crystallographic
studies to form part of the metal-binding site [1]. The HEXXH motif is 
relatively common, but can be more stringently defined for metallo-
proteases as abXHEbbHbc, where a is most often valine or threonine and 
forms part of the S1' subsite in thermolysin and neprilysin, b is an
uncharged residue, and c a hydrophobic residue. Proline is never found
in this site, possibly because it would break the helical structure 
adopted by this motif in metalloproteases [1].
 
Metalloproteases can be split into five groups on the basis of their metal-
binding residues: the first three contain the HEXXH motif, the other two
do not [1]. In the first group, a glutamic acid completes the active site -
these are termed HEXXH+E: all families in this group show some sequence
relationship and have been assigned to clan MA [1]. The second group, which
have a third histidine as the extra metal-binding residue, are termed
HEXXH+H and are grouped into clan MB on the basis of their inter-relation-
ship[1]. In the third group, the additional metal-binding residues are
unidentified. The fourth group is diverse - the metal-binding residues are
known but do not form the HEXXH motif. And the fifth group comprises the
remaining families where the metal-binding residues are as yet unknown [1,2].
 
Members of the M50 metallopeptidase family include mamalian sterol-regulatory
element binding protein (SREBP) site 2 proteases and various hypothetical 
bacterial homologues [3]. SREBPs are membrane-bound transcription factors 
that regulate cholesterol and fatty acid synthesis in mamalian cells. In
order to be activated, the N-terminal domain must be released from the
membrane into the nucleus by proteolytic cleavage at two sites: the first
site is located within the lumen of the endoplasmic reticulum, and second 
site within the transmembrane (TM) region. SREBP site 2 proteases act at 
this second, TM, site. In humans, the protease is encoded by the S2P gene
[4]. Once the SREBP has been released into the nucleus, it acts to stimulate
transcription of genes involved in lipid metabolism. The site 2 protease has
been shown to act on SREBP at the Leu522-Ser523 bond [5].
 
SREBPS2PTASE is a 4-element fingerprint that provides a signature for the
mamalian sterol-regulatory element binding protein site 2 protease and its
hypothetical bacterial homologues (the M50 metallopeptidase family). The
fingerprint was derived from an initial alignment of 8 sequences: the motifs
were drawn from conserved regions surrounding the active site - motif 2 
includes the region encoded by the PROSITE pattern ZINC_PROTEASE (PS00142),
which describes the HEXXH active site. A single iteration on OWL31.1 was
required to reach convergence, no further sequences being identified beyond
the starting set. 
 
An update on SPTR37_9f identified a true set of 8 sequences, and 2
partial matches.
Summary Information
8 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
48888
30000
20000
1234
True Positives
O27421        O28947        O43462        O54862        
O57994 O65444 P95972 Y971_METJA
Sequence Titles
O27421      CONSERVED PROTEIN - METHANOBACTERIUM THERMOAUTOTROPHICUM. 
O28947 CONSERVED HYPOTHETICAL PROTEIN - ARCHAEOGLOBUS FULGIDUS.
O43462 S2P - HOMO SAPIENS (HUMAN).
O54862 S2P - CRICETULUS GRISEUS (CHINESE HAMSTER).
O57994 377AA LONG HYPOTHETICAL PROTEIN - PYROCOCCUS HORIKOSHII.
O65444 HYPOTHETICAL 40.3 KD PROTEIN - ARABIDOPSIS THALIANA (MOUSE-EAR CRESS).
P95972 ORF C04034 - SULFOLOBUS SOLFATARICUS.
Y971_METJA HYPOTHETICAL PROTEIN MJ0971 - METHANOCOCCUS JANNASCHII.
Scan History
OWL31_1    2  600  NSINGLE    
SPTR37_9f 2 350 NSINGLE
Initial Motifs
Motif 1  width=20
Element Seqn Id St Int Rpt
VDIPGSPVYVPLGYGIIGLA H69048 102 102 -
GFSPSTRVSLSGIAYVLVST ATF1C1222 99 99 -
PIIPGVTISISQLPYILLAI S75400 123 123 -
VVVPGINLPVNQLTYFFAAV AF019611 136 136 -
VVVPGINLPVNQLTYFFTAV AF019612 145 145 -
VFLFGDVIPWIPGIIALLIA Y971_METJA 100 100 -
LVIPGVTIPLVYGLIALAIL A71450 105 105 -
LLLPGVNPFIPIVWGTIGLV A69415 110 110 -

Motif 2 width=15
Element Seqn Id St Int Rpt
VIVHELSHGFVARSE A71450 125 0 -
LIVHEFSHAILCRVE A69415 132 2 -
VSVHELGHALAAASE ATF1C1222 122 3 -
VAIHEIFHALSATSN S75400 146 3 -
GVVHEIGHGIAAIRE AF019611 159 3 -
ISVHELAHGIFAKSF Y971_METJA 120 0 -
GVVHEIGHGIAAIRE AF019612 168 3 -
IVVHEFAHGILARLE H69048 124 2 -

Motif 3 width=16
Element Seqn Id St Int Rpt
VTVKSLGVILALIPIG A69415 148 1 -
VRIKSIGLLLLAILPG H69048 140 1 -
IPLKSVGLLLFIIIPG A71450 141 1 -
IQMEYIAVFIAAIFPG ATF1C1222 138 1 -
VKVKNGGVLLLGIFPG S75400 162 1 -
VRFNGFGIFLFIIYPG AF019611 175 1 -
VRFNGFGIFLFIIYPG AF019612 184 1 -
IKVKSSGILLLLGLPL Y971_METJA 136 1 -

Motif 4 width=13
Element Seqn Id St Int Rpt
GLVAFDNDVLQSL ATF1C1222 154 0 -
AFVEPDEDDFNKS S75400 178 0 -
AFVDLFTTHLQLI AF019611 191 0 -
AFVDLFTTHLQLI AF019612 200 0 -
AFVEPDEDQLKKA A71450 157 0 -
AFVEPDEEDIKKI H69048 156 0 -
GAFVELGDEFKTA Y971_METJA 152 0 -
GFAEPEEKEIMDK A69415 164 0 -
Final Motifs
Motif 1  width=20
Element Seqn Id St Int Rpt
VVVPGINLPVNQLTYFFAAV O54862 136 136 -
VVVPGINLPVNQLTYFFTAV O43462 145 145 -
LVIPGVTIPLVYGLIALAIL O57994 105 105 -
VDIPGSPVYVPLGYGIIGLA O27421 102 102 -
PIIPGVTISISQLPYILLAI P95972 123 123 -
LLLPGVNPFIPIVWGTIGLV O28947 110 110 -
VFLFGDVIPWIPGIIALLIA Y971_METJA 100 100 -
GFSPSTRVSLSGIAYVLVST O65444 99 99 -

Motif 2 width=15
Element Seqn Id St Int Rpt
GVVHEIGHGIAAIRE O54862 159 3 -
GVVHEIGHGIAAIRE O43462 168 3 -
VIVHELSHGFVARSE O57994 125 0 -
IVVHEFAHGILARLE O27421 124 2 -
VAIHEIFHALSATSN P95972 146 3 -
LIVHEFSHAILCRVE O28947 132 2 -
ISVHELAHGIFAKSF Y971_METJA 120 0 -
VSVHELGHALAAASE O65444 122 3 -

Motif 3 width=16
Element Seqn Id St Int Rpt
VRFNGFGIFLFIIYPG O54862 175 1 -
VRFNGFGIFLFIIYPG O43462 184 1 -
IPLKSVGLLLFIIIPG O57994 141 1 -
VRIKSIGLLLLAILPG O27421 140 1 -
VKVKNGGVLLLGIFPG P95972 162 1 -
VTVKSLGVILALIPIG O28947 148 1 -
IKVKSSGILLLLGLPL Y971_METJA 136 1 -
IQMEYIAVFIAAIFPG O65444 138 1 -

Motif 4 width=13
Element Seqn Id St Int Rpt
AFVDLFTTHLQLI O54862 191 0 -
AFVDLFTTHLQLI O43462 200 0 -
AFVEPDEDQLKKA O57994 157 0 -
AFVEPDEEDIKKI O27421 156 0 -
AFVEPDEDDFNKS P95972 178 0 -
GFAEPEEKEIMDK O28947 164 0 -
GAFVELGDEFKTA Y971_METJA 152 0 -
GLVAFDNDVLQSL O65444 154 0 -