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PR01221

Identifier
MAJORURINARY  [View Relations]  [View Alignment]  
Accession
PR01221
No. of Motifs
7
Creation Date
30-NOV-1999
Title
Rodent urinary protein signature
Database References
PRINTS; PR00179 LIPOCALIN
INTERPRO; IPR002971
PDB; 1MUP
SCOP; 1MUP
CATH; 1MUP
Literature References
1. PERVAIS, S. AND BREW, K. 
Homology of beta-lactoglobulin, serum retinol-binding protein and 
protein HC.
SCIENCE 228 335-337 (1985).
 
2. FLOWER, D.R.
The Lipocalin protein family: structure and function.
BIOCHEM.J. 318 1-14 (1996).
 
3. FLOWER, D.R., NORTH, A.C.T. AND ATTWOOD, T.K.
Structural and sequence relationships in the lipocalins and related
proteins.
PROTEIN SCI. 2 753-761 (1993). 
 
4. FLOWER, D.R.
Multiple molecular recognition properties of the lipocalin protein family.
J.MOL.REC. 8 185-195 (1995).
 
5. BOCSKEI, Z., GROOM, C.R., FLOWER, D.R., WRIGHT, C.E., PHILLIPS, S.E.V., 
CAVAGGIONI, A., FINDLAY, J.B.C. AND NORTH, A.C.T.
Pheromone Binding to Two Rodent Urinary Proteins Revealed by X-Ray
Crystallography.
NATURE 360 186-190 (1992).

Documentation
The lipocalins are a diverse, interesting, yet poorly understood family of 
proteins composed, in the main, of extracellular ligand-binding proteins
displaying high specificity for small hydrophobic molecules [1,2]. Functions
of these proteins include transport of nutrients, control of cell regula-
tion, pheromone transport, cryptic colouration and the enzymatic synthesis
of prostaglandins.
   
The crystal structures of several lipocalins have been solved and show a 
novel 8-stranded anti-parallel beta-barrel fold well conserved within the
family. Sequence similarity within the family is at a much lower level and
would seem to be restricted to conserved disulphides and 3 motifs, which
form a juxtaposed cluster that may act as a common cell surface receptor
site [2]. By contrast, at the more variable end of the fold are found an 
internal ligand binding site and a putative surface for the formation of 
macromolecular complexes [4]. The anti-parallel beta-barrel fold is also
exploited by the fatty acid-binding proteins (which function similarly by
binding small hydrophobic molecules), by avidin and the closely related
metalloprotease inhibitors, and by triabin. Similarity at the sequence 
level, however, is less obvious, being confined to a single short 
N-terminal motif.
 
The lipocalin family can be subdivided into kernal and outlier sets. The
kernal lipocalins form the largest self-consistent group (see LIPOCALIN
signature). The outlier lipocalins form several smaller distinct subgroups: 
the OBPs, the von Ebner's gland proteins, alpha-1-acid glycoproteins, 
tick histamine binding proteins and the nitrophorins.
 
Rodent urinary proteins (mouse MUPs and rat alpha-2u globulins) are the  
major protein components of rodent urine and transport pheromones [5].
Rodent urine contains an unusually large amount of protein; this phenomenon 
has been studied extensively in both rats and mice. The major site of MUP
synthesis is the liver; the protein is secreted by the liver into serum, 
where it circulates at relatively low levels before being rapidly filtered
by the kidney and excreted. Expression of MUP mRNA is under different 
developmental and hormonal control in different tissues. However, 
constitutive expression of major urinary protein has been demonstrated in 
the salivary and lachrymal glands.
 
The sex-dependent expression of MUP (adult male mice secrete 5-20 times 
as much MUP as do females) and its ability to bind a number of odorant 
molecules is consistent with the suggestion that MUP acts as a pheromone
transporter; the protein may be excreted into the urine carrying a bound
pheromone, which is released as the urine dries and the protein denatures.
This proposal is strongly supported by the work of Bacchini and colleagues,
who have successfully purified MUP from mouse urine with bound ligands. They
identified three components from the total ligand extracted from the 
purified protein: the largest proportion (~70%) was 2-(s-butyl)thiazoline,
with 2,3-dehydroexobrevicomin and 4-(ethyl)phenol comprising minor fractions
of ~15% each. However, only ~40% of protein contained bound ligand. The
first two of these compounds are known to have pheromone activity in male
rat urine, eliciting many sexually related responses in female rats. A 
recent report has shown that MUP, acting via the vomeronasal organ after 
appropriate physical contact with male mouse urine in their environment, can
accelerate the onset of puberty in female mice. Interestingly, this seems to
be a function of the protein itself; MUP devoid of ligands, either by 
extraction or competitive displacement, is still active, while an organic 
extract containing these volatile ligands shows no activity. Moreover, a 
peptide corresponding to the N-terminus of MUP is also active, suggesting 
that MUP is not only a carrier of pheromones, but also a pheromone itself.
The crystal structure of MUP has been solved [5] and is known to be a 
member of the lipocalin family. 
 
Alpha-2u-globulin, a close homologue of MUP, accounts for 30-50% of total
excreted protein in adult male rat urine. As its electrophoretic mobility
is similar to that of serum a2 globulin, it was named `alpha-2u-globulin',
the subscript `u' denoting its origin in urine. Alpha-2u-globulin is 
secreted into the plasma by a number of tissues, where it circulates before
filtration through the kidney; between 20 and 50% is reabsorbed by the
proximal tubule of the nephron, the rest being excreted. Although the exact
physiological role of alpha-2u-globulin is unclear, there is circumstantial
evidence that it functions in pheromone transport. This is consistent with
its observed binding properties, its close similarity with MUP and the known
properties of male rat urine. For example, acute exposure to many important
industrial and environmental chemicals, including components of unleaded 
petrol, causes a toxic syndrome, known as a2u globulin nephropathy, in the
kidney of adult male rats. This syndrome is characterised by an excessive
accumulation, in proximal-tubule epithelial cells, of lysosomal protein
droplets composed of large amounts of alpha-2u-globulin, and the degeneration
and necrosis of cells lining the proximal tubule. Chronic exposure leads to
an escalating progression of symptoms, often resulting in kidney failure and
death. 
 
MAJORURINARY is a 7-element fingerprint that provides a signature for rodent
urinary proteins. The fingerprint was derived from an initial alignment of
4 sequences: the motifs were drawn from conserved regions spanning virtually
the full alignment length - motif 1 covers the N-terminal peptide and 310
helix; motif 2, which includes the region encoded by PROSITE pattern
LIPOCALIN (PS00213) and corresponds to the first LIPOCALIN fingerprint motif,
spans the first beta-strand; motif 3 spans the distal region of the large
loop L1 and strands 2 and 3; motif 4 covers strand 4 and the anterior region
of strand 5; motif 5, which spans the C-terminus of strand 6 and strand 7,
corresponds to the second motif of the LIPOCALIN fingerprint; motif 6, which
spans strand 8 and the N-terminus of the main C-terminal alpha-helix, is 
similar to the third LIPOCALIN motif; and motif 7 spans the C-terminal
peptide and includes the short beta-strand 9. Two iterations on SPRT37_10f
were required to reach convergence, at which point a true set comprising 11
sequences was identified. A single partial match was also found, horse 
allergen 1 protein, which matches motifs 2, 4, 6 and 7.
Summary Information
  11 codes involving  7 elements
0 codes involving 6 elements
0 codes involving 5 elements
1 codes involving 4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
711111111111111
60000000
50000000
40101011
30000000
20000000
1234567
True Positives
MUP1_MOUSE    MUP2_MOUSE    MUP4_MOUSE    MUP5_MOUSE    
MUP6_MOUSE MUPM_MOUSE MUP_RAT Q61921
Q63024 Q63025 Q63213
True Positive Partials
Codes involving 4 elements
ALL1_HORSE
Sequence Titles
MUP1_MOUSE  MAJOR URINARY PROTEIN 1 PRECURSOR (MUP 1) - MUS MUSCULUS (MOUSE). 
MUP2_MOUSE MAJOR URINARY PROTEIN 2 PRECURSOR (MUP 2) - MUS MUSCULUS (MOUSE).
MUP4_MOUSE MAJOR URINARY PROTEIN 4 PRECURSOR (MUP 4) - MUS MUSCULUS (MOUSE).
MUP5_MOUSE MAJOR URINARY PROTEIN 5 PRECURSOR (MUP 5) - MUS MUSCULUS (MOUSE).
MUP6_MOUSE MAJOR URINARY PROTEIN 6 PRECURSOR (MUP 6) (ALPHA-2U-GLOBULIN) (GROUP 1, BS6) (ALLERGEN MUS M 1) - MUS MUSCULUS (MOUSE).
MUPM_MOUSE MINOR MAJOR URINARY PROTEIN 15 PRECURSOR (NON-GROUP 1/GROUP 2 MUP15) (MUP3) - MUS MUSCULUS (MOUSE).
MUP_RAT MAJOR URINARY PROTEIN PRECURSOR (MUP) (ALPHA-2U-GLOBULIN) (15.5 KD FATTY ACID BINDING PROTEIN) (15.5 KD FABP) - RATTUS NORVEGICUS (RAT).
Q61921 MAJOR URINARY PROTEIN - MUS MUSCULUS (MOUSE).
Q63024 RAT ALPHA-2U-GLOBULIN (L TYPE) - RATTUS NORVEGICUS (RAT).
Q63025 RAT ALPHA-2U-GLOBULIN (S TYPE) - RATTUS NORVEGICUS (RAT).
Q63213 ALPHA-2U GLOBULIN (RAT SALIVARY GLAND (ALPHA)2(MU) GLOBULIN, TYPE 1) - RATTUS NORVEGICUS (RAT).

ALL1_HORSE MAJOR ALLERGEN EQU C 1 PRECURSOR - EQUUS CABALLUS (HORSE).
Scan History
SPTR37_10f 2  15   NSINGLE    
Initial Motifs
Motif 1  width=15
Element Seqn Id St Int Rpt
HAEEASSTGRNFNVE Q61921 15 15 -
HAEEATSKGQNLNVE MUP4_MOUSE 15 15 -
HAEEASFERGNLDVD Q63213 18 18 -
HAEESSSMERNFNVE MUPM_MOUSE 21 21 -

Motif 2 width=19
Element Seqn Id St Int Rpt
NGEWHTIILAFDKREKIED Q61921 32 2 -
NGEWFSILLASDKREKIEE MUP4_MOUSE 32 2 -
NGDWFSIVVASDKREKIEE Q63213 35 2 -
SGYWFSIAEASYEREKIEE MUPM_MOUSE 38 2 -

Motif 3 width=22
Element Seqn Id St Int Rpt
IHVLENSLVLKFHTVRDEECSE Q61921 61 10 -
IHVLENSLAFKFHTVIDGECSE MUP4_MOUSE 61 10 -
IDVLENSLGFTFRIKENGVCTE Q63213 64 10 -
ITVLENSLVFKFHLIVNEECTE MUPM_MOUSE 67 10 -

Motif 4 width=13
Element Seqn Id St Int Rpt
GEYSVTYDGFNTF Q61921 94 11 -
GEYSVMYDGFNTF MUP4_MOUSE 94 11 -
GEYFVEYDGENTF Q63213 97 11 -
GIYYMNYDGFNTF MUPM_MOUSE 100 11 -

Motif 5 width=16
Element Seqn Id St Int Rpt
IPKTDYDNFLMAHLIN Q61921 108 1 -
ILKTDYDNYIMFHLIN MUP4_MOUSE 108 1 -
ILKTDYDNYVMFHLVN Q63213 111 1 -
ILKTDYDNYIMIHLIN MUPM_MOUSE 114 1 -

Motif 6 width=22
Element Seqn Id St Int Rpt
TFQLMGLYGREPDLSSDIKERF Q61921 129 5 -
TFQLMELYGRKADLNSDIKEKF MUP4_MOUSE 129 5 -
TFQLMELYGRTKDLSSDIKEKF Q63213 132 5 -
TFQLMELYGREPDLSLDIKEKF MUPM_MOUSE 135 5 -

Motif 7 width=18
Element Seqn Id St Int Rpt
HGILRENIIDLSNANRCL Q61921 157 6 -
HGIIKENIIDLTKTNRCL MUP4_MOUSE 157 6 -
HGITRDNIIDLTKTDRCL Q63213 160 6 -
HGIIRENIIDLTNVNRCL MUPM_MOUSE 163 6 -
Final Motifs
Motif 1  width=15
Element Seqn Id St Int Rpt
HAEEASSTGRNFNVE MUP1_MOUSE 17 17 -
HAEEASSTGRNFNVE MUP6_MOUSE 17 17 -
HAEEASSTGRNFNVE MUP2_MOUSE 17 17 -
HAEEASSTGRNFNVE Q61921 15 15 -
HAEEASSERQNFNVE MUP5_MOUSE 17 17 -
HAEEASSTRGNLDVA MUP_RAT 18 18 -
HAEEASSTRGNLDVD Q63024 18 18 -
HAEEASSTRGNLDVD Q63025 18 18 -
HAEEATSKGQNLNVE MUP4_MOUSE 15 15 -
HAEEASFERGNLDVD Q63213 18 18 -
HAEESSSMERNFNVE MUPM_MOUSE 21 21 -

Motif 2 width=19
Element Seqn Id St Int Rpt
NGEWHTIILASDKREKIED MUP1_MOUSE 34 2 -
NGEWHTIILASDKREKIED MUP6_MOUSE 34 2 -
NGEWHTIILASDKREKIED MUP2_MOUSE 34 2 -
NGEWHTIILAFDKREKIED Q61921 32 2 -
NGKWFSILLASDKREKIEE MUP5_MOUSE 34 2 -
NGDWFSIVVASNKREKIEE MUP_RAT 35 2 -
NGDWFSIVVASDKREKIEE Q63024 35 2 -
NGDWFSIVVASDKREKIEE Q63025 35 2 -
NGEWFSILLASDKREKIEE MUP4_MOUSE 32 2 -
NGDWFSIVVASDKREKIEE Q63213 35 2 -
SGYWFSIAEASYEREKIEE MUPM_MOUSE 38 2 -

Motif 3 width=22
Element Seqn Id St Int Rpt
IHVLENSLVLKFHTVRDEECSE MUP1_MOUSE 63 10 -
IHVLENSLVLKFHTVRDEECSE MUP6_MOUSE 63 10 -
IHVLEKSLVLKFHTVRDEECSE MUP2_MOUSE 63 10 -
IHVLENSLVLKFHTVRDEECSE Q61921 61 10 -
IDVLENSLAFKFHTVIDEECTE MUP5_MOUSE 63 10 -
IDVLENSLGFKFRIKENGECRE MUP_RAT 64 10 -
IDVLENSLGFKFRIKENGECRE Q63024 64 10 -
IDVLENSLGFKFRIKENGECRE Q63025 64 10 -
IHVLENSLAFKFHTVIDGECSE MUP4_MOUSE 61 10 -
IDVLENSLGFTFRIKENGVCTE Q63213 64 10 -
ITVLENSLVFKFHLIVNEECTE MUPM_MOUSE 67 10 -

Motif 4 width=13
Element Seqn Id St Int Rpt
GEYSVTYDGFNTF MUP1_MOUSE 96 11 -
GEYSVTYDGFNTF MUP6_MOUSE 96 11 -
GEYSVTYDGFNTF MUP2_MOUSE 96 11 -
GEYSVTYDGFNTF Q61921 94 11 -
GEYSVTYDGFNTF MUP5_MOUSE 96 11 -
GEYFVEYDGGNTF MUP_RAT 97 11 -
GEYFVEYDGGNTF Q63024 97 11 -
GEYFVEYDGGNTF Q63025 97 11 -
GEYSVMYDGFNTF MUP4_MOUSE 94 11 -
GEYFVEYDGENTF Q63213 97 11 -
GIYYMNYDGFNTF MUPM_MOUSE 100 11 -

Motif 5 width=16
Element Seqn Id St Int Rpt
IPKTDYDNFLMAHLIN MUP1_MOUSE 110 1 -
IPKTDYDNFLMAHLIN MUP6_MOUSE 110 1 -
IPKTDYDNFLMAHLIN MUP2_MOUSE 110 1 -
IPKTDYDNFLMAHLIN Q61921 108 1 -
ILKTDYDNYIMFHLIN MUP5_MOUSE 110 1 -
ILKTDYDRYVMFHLIN MUP_RAT 111 1 -
ILKTDYDRYVMFHLIN Q63024 111 1 -
ILKTDYDRYVMFHLIN Q63025 111 1 -
ILKTDYDNYIMFHLIN MUP4_MOUSE 108 1 -
ILKTDYDNYVMFHLVN Q63213 111 1 -
ILKTDYDNYIMIHLIN MUPM_MOUSE 114 1 -

Motif 6 width=22
Element Seqn Id St Int Rpt
TFQLMGLYGREPDLSSDIKERF MUP1_MOUSE 131 5 -
TFQLMGLYGREPDLMSDIKERF MUP6_MOUSE 131 5 -
TFQLMGLYGREPDLSSDIKERF MUP2_MOUSE 131 5 -
TFQLMGLYGREPDLSSDIKERF Q61921 129 5 -
NFQLMELFGREPDLSSDIKEKF MUP5_MOUSE 131 5 -
TFQLMVLYGRTKDLSSDIKEKF MUP_RAT 132 5 -
TFQAMVLYGRTKDLSSDIKEKF Q63024 132 5 -
TFQAMVLYGRTKDLSSDIKEKF Q63025 132 5 -
TFQLMELYGRKADLNSDIKEKF MUP4_MOUSE 129 5 -
TFQLMELYGRTKDLSSDIKEKF Q63213 132 5 -
TFQLMELYGREPDLSLDIKEKF MUPM_MOUSE 135 5 -

Motif 7 width=18
Element Seqn Id St Int Rpt
HGILRENIIDLSNANRCL MUP1_MOUSE 159 6 -
HGILRENIIDLSNANRCL MUP6_MOUSE 159 6 -
HGILRENIIDLSNANRCL MUP2_MOUSE 159 6 -
HGILRENIIDLSNANRCL Q61921 157 6 -
HGIVRENIIDLSNANRCL MUP5_MOUSE 159 6 -
HGITRDNIIDLTKTDRCL MUP_RAT 160 6 -
HGITRDNIIDLTKTDHCL Q63024 160 6 -
HGITRDNIIDLTKTDHCL Q63025 160 6 -
HGIIKENIIDLTKTNRCL MUP4_MOUSE 157 6 -
HGITRDNIIDLTKTDRCL Q63213 160 6 -
HGIIRENIIDLTNVNRCL MUPM_MOUSE 163 6 -