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PR01215

Identifier
A1MCGLOBULIN  [View Relations]  [View Alignment]  
Accession
PR01215
No. of Motifs
6
Creation Date
31-AUG-1999
Title
Alpha-1-microglobulin signature
Database References
PRINTS; PR00179 LIPOCALIN
INTERPRO; IPR002968
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. AKERSTROM, B. AND LOGDBERG, L. 
An intriguing member of the lipocalin protein family: alpha 1-microglobulin.
TRENDS BIOCHEM.SCI. 15 240-243 (1990).

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.
 
Alpha-1-microglobulin (A1M), also known as protein HC (for Heterogeneous 
Charge), is a low molecular weight protein component of plasma that has 
been studied extensively since its initial discovery in pathological human
urine. Although much is now known of its structure and properties, the
function and physiological role of A1M remains unclear, although the weight
of evidence suggests that it functions in the regulation of the immune
system [5]. 
 
A1M is known to exist in both a free form and complexed to other macro-
molecules: immunoglobulin A (IgA) in humans and alpha-1-inhibitor-3 in the
rat. Free A1M is a monomeric protein composed of one 188 residue polypeptide
and contains three cysteines, two of which (residues 75 and 173) form a 
conserved intra-molecuklar disulphide link [5]. A1M is glycosylated by 
three separate carbohydrate chains: two complex carbohydrates are N-linked 
to asparagines at residues 17 and 96, and the other simple carbohydrate is
O-linked to threonine at position 5. These three saccharide chains represent
3%, 12% and 7% respectively of the total molecular mass of A1M; thus 22% of 
the total molecular mass of the protein is derived from carbohydrate. Free
A1M is extremely heterogeneous in charge (appearing as a smear rather than
a sharp band in electrophoresis) and cannot be easily separated from a 
tightly-associated chromophore, which is responsible for the characteristic 
yellow-brown fluorescence of the free protein in aqueous solution [5]. 
Moreover, this chromophoric group, which is also responsible for the 
observed charge heterogeneity of A1M, is covalently bound to the free
cysteine residue at position 34. Hexane extraction of purified A1M 
indicates that the protein also binds retinol as a major (but not its only)
ligand, but that this is probably distinct from the its covalent chromophore.
 
The glycosylation is different between species. The principal sites of A1M 
synthesis are the liver and kidney. Half of all human plasma A1M (about 
0.03mg/ml) forms a 1:1 complex with about 5% of plasma immunoglobulin A: 
the resulting macromolecular complex has a molecular weight of 200000, and
a plasma concentration of 0.3mg/ml. It can exhibit both antibody activity 
and affect many of the biological actions of free A1M [5]. It has also been
shown that the components of this complex are linked, by a covalent
association of unknown type, between part of the C-terminal nine residues
of IgA and some part of A1M prior to Cys 75. The A1M-IgA complex does not
exhibit the charge heterogeneity and yellow-brown fluorescence of free A1M.
This would seem to imply that the chromophoric group joined to cysteine 34
is involved in this covalent link. More recently, a corresponding high 
molecular weight complex involving A1M has been isolated from rat serum: 
rather than IgA, this complex contains alpha-1-inhibitor 3 (A1I3), a variant
of rat plasma alpha-macroglobulin. This 1:1 A1M:A1I3 complex, molecular 
weight ~266,000, represents 1-3% of total plasma A1I3 and around 60% of 
plasma A1M. The lack of charge heterogeneity and fluorescence would suggest
that the complex is also covalently associated.
 
A1M has many affects on the immune system [5]: it inhibits stimulation of
cultured lymphocytes by protein antigens; it can induce cell division of
lymphocytes, a mitogenic effect that can either be enhanced or inhibited by
the action of other plasma components; it inhibits neutrophil granulocyte
migration in vitro; and it inhibits chemotaxis (cell migration against a
gradient of attractive agent). The recent identification of cell surface
receptors for A1M [5] may indicate the mechanism by which the protein
exerts its physiological effects.
 
A1MCGLOBULIN is a 6-element fingerprint that provides a motif for alpha-1-
microglobulin. The fingerprint was derived from an initial alignment of 3 
sequences: the motifs were drawn from conserved regions spanning virtually
the full alignment length - motif 1 includes a GxW triplet, which forms 
part of the first beta-strand (cf. the first motif of signature LIPOCALIN 
and PROSITE pattern LIPOCALIN (PS00213)); motif 5 lies in a conserved region
of the barrel involving beta-strands 6 and 7 and the loop between them, and
corresponds closely to the second motif of the lipocalin fingerprint; and
motif 6 encodes a similar region to the third lipocalin motif, which lies
in a structurally conserved region involving the final strand and part of 
the loop linking it to the C-terminal alpha-helix. Two iterations on 
SPRT37_10f were required to reach convergence, at which point a true set
comprising 8 sequences was identified.
Summary Information
8 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
6888888
5000000
4000000
3000000
2000000
123456
True Positives
AMBP_BOVIN    AMBP_HUMAN    AMBP_MERUN    AMBP_MESAU    
AMBP_MOUSE AMBP_RAT O70160 P70004
Sequence Titles
AMBP_BOVIN  AMBP PROTEIN PRECURSOR [CONTAINS: ALPHA-1-MICROGLOBULIN; INTER-ALPHA- TRYPSIN INHIBITOR LIGHT CHAIN (ITI-LC) (BIKUNIN) (HI-30) (BI-14) (CUMULUS EXTRACELLULAR MATRIX STABILIZING FACTOR) (ESF)] - BOS TAURUS (BOVINE). 
AMBP_HUMAN AMBP PROTEIN PRECURSOR [CONTAINS: ALPHA-1-MICROGLOBULIN (PROTEIN HC) (COMPLEX-FORMING GLYCOPROTEIN HETEROGENEOUS IN CHARGE); INTER-ALPHA- TRYPSIN INHIBITOR LIGHT CHAIN (ITI-LC) (BIKUNIN) (HI-30)] - HOMO SAPIENS (HUMAN).
AMBP_MERUN AMBP PROTEIN PRECURSOR [CONTAINS: ALPHA-1-MICROGLOBULIN; INTER-ALPHA- TRYPSIN INHIBITOR LIGHT CHAIN (ITI-LC) (BIKUNIN) (HI-30)] - MERIONES UNGUICULATUS (MONGOLIAN JIRD).
AMBP_MESAU AMBP PROTEIN PRECURSOR [CONTAINS: ALPHA-1-MICROGLOBULIN; INTER-ALPHA- TRYPSIN INHIBITOR LIGHT CHAIN (ITI-LC) (BIKUNIN) (HI-30)] - MESOCRICETUS AURATUS (GOLDEN HAMSTER).
AMBP_MOUSE AMBP PROTEIN PRECURSOR [CONTAINS: ALPHA-1-MICROGLOBULIN; INTER-ALPHA- TRYPSIN INHIBITOR LIGHT CHAIN (ITI-LC) (BIKUNIN) (HI-30)] - MUS MUSCULUS (MOUSE).
AMBP_RAT AMBP PROTEIN PRECURSOR [CONTAINS: ALPHA-1-MICROGLOBULIN; INTER-ALPHA- TRYPSIN INHIBITOR LIGHT CHAIN (ITI-LC) (BIKUNIN) (HI-30)] - RATTUS NORVEGICUS (RAT).
O70160 ALPHA-1-MICROGLOBULIN/BIKUNIN - CAVIA PORCELLUS (GUINEA PIG).
P70004 ALPHA1-MICROGLOBULIN/BIKUNIN PRECURSOR (AMBP) - XENOPUS LAEVIS (AFRICAN CLAWED FROG).
Scan History
SPTR37_10f 2  20   NSINGLE    
Initial Motifs
Motif 1  width=14
Element Seqn Id St Int Rpt
QENFNESRIYGKWF AMBP_MESAU 31 31 -
QENFIESLIYGKWF AMBP_MERUN 31 31 -
QENFNISRIYGKWY AMBP_HUMAN 32 32 -

Motif 2 width=12
Element Seqn Id St Int Rpt
LAVGSTCPWLSR AMBP_MESAU 46 1 -
LAVGSTCPWLRR AMBP_MERUN 46 1 -
LAIGSTCPWLKK AMBP_HUMAN 47 1 -

Motif 3 width=16
Element Seqn Id St Int Rpt
CEEVSGTYEKTDMDGK AMBP_MESAU 90 32 -
CEEISGAYEKTDIDGK AMBP_MERUN 90 32 -
CEETSGAYEKTDTDGK AMBP_HUMAN 91 32 -

Motif 4 width=20
Element Seqn Id St Int Rpt
KWNVTLESYVVHTNYDEYAI AMBP_MESAU 112 6 -
KWNITLETYVVHTNYDEYAI AMBP_MERUN 112 6 -
KWNITMESYVVHTNYDEYAI AMBP_HUMAN 113 6 -

Motif 5 width=22
Element Seqn Id St Int Rpt
TITAKLYGREPQLRDSLLQEFR AMBP_MESAU 144 12 -
TITLKLYGREPKLRDSLLLEFR AMBP_MERUN 144 12 -
TITAKLYGRAPQLRETLLQDFR AMBP_HUMAN 145 12 -

Motif 6 width=20
Element Seqn Id St Int Rpt
GIPENSIVFMEDRGECVPGD AMBP_MESAU 172 6 -
GIPENSIVFMADKGECVPGD AMBP_MERUN 172 6 -
GIPEDSIFTMADRGECVPGE AMBP_HUMAN 173 6 -
Final Motifs
Motif 1  width=14
Element Seqn Id St Int Rpt
QENFNEARIYGKWF AMBP_RAT 31 31 -
QENFNESRIYGKWF AMBP_MESAU 31 31 -
QENFSESRIYGKWY AMBP_MOUSE 31 31 -
QENFIESLIYGKWF AMBP_MERUN 31 31 -
QENFNISRIYGKWY AMBP_HUMAN 32 32 -
QENFDLSRIYGKWF AMBP_BOVIN 32 32 -
QENFDESRMYGKWY O70160 32 32 -
QENFDLQRIYGKWY P70004 31 31 -

Motif 2 width=12
Element Seqn Id St Int Rpt
LAVGSTCPWLRR AMBP_RAT 46 1 -
LAVGSTCPWLSR AMBP_MESAU 46 1 -
LAVGSTCPWLSR AMBP_MOUSE 46 1 -
LAVGSTCPWLRR AMBP_MERUN 46 1 -
LAIGSTCPWLKK AMBP_HUMAN 47 1 -
VAVGSTCPWLKR AMBP_BOVIN 47 1 -
LAIGSTCPWLKR O70160 47 1 -
IAIGSTCKWLKH P70004 46 1 -

Motif 3 width=16
Element Seqn Id St Int Rpt
CEEISGVYQKTDIDGK AMBP_RAT 90 32 -
CEEVSGTYEKTDMDGK AMBP_MESAU 90 32 -
CEEITGAYQKTDIDGK AMBP_MOUSE 90 32 -
CEEISGAYEKTDIDGK AMBP_MERUN 90 32 -
CEETSGAYEKTDTDGK AMBP_HUMAN 91 32 -
CESISGTYEKTSADGK AMBP_BOVIN 91 32 -
CERTSGFYEKTDTAGK O70160 91 32 -
CSQIVGSYQKTETPGK P70004 90 32 -

Motif 4 width=20
Element Seqn Id St Int Rpt
KWNATLESYVVHTNYDEYAI AMBP_RAT 112 6 -
KWNVTLESYVVHTNYDEYAI AMBP_MESAU 112 6 -
KWNITLESYVVHTNYDEYAI AMBP_MOUSE 112 6 -
KWNITLETYVVHTNYDEYAI AMBP_MERUN 112 6 -
KWNITMESYVVHTNYDEYAI AMBP_HUMAN 113 6 -
KWNITMESYVVHTNYDEYAI AMBP_BOVIN 113 6 -
KWNLTMESYVVHTNYDEYAT O70160 113 6 -
RWGTTIQNYIVFTNYNEYVI P70004 112 6 -

Motif 5 width=22
Element Seqn Id St Int Rpt
TITAKLYGREPQLRDSLLQEFR AMBP_RAT 144 12 -
TITAKLYGREPQLRDSLLQEFR AMBP_MESAU 144 12 -
TITAKLYGREPQLRDSLLQEFK AMBP_MOUSE 144 12 -
TITLKLYGREPKLRDSLLLEFR AMBP_MERUN 144 12 -
TITAKLYGRAPQLRETLLQDFR AMBP_HUMAN 145 12 -
TITVKLYGREPQLRESLLEEFR AMBP_BOVIN 145 12 -
TITAKLYGREPQLRDSLLQGFR O70160 145 12 -
TTTVKLYGRSPDLRPTLVDEFR P70004 143 11 -

Motif 6 width=20
Element Seqn Id St Int Rpt
GIPENSIVFMADRGECVPGD AMBP_RAT 172 6 -
GIPENSIVFMEDRGECVPGD AMBP_MESAU 172 6 -
GISENSIIFMPDRGECVPGD AMBP_MOUSE 172 6 -
GIPENSIVFMADKGECVPGD AMBP_MERUN 172 6 -
GIPEDSIFTMADRGECVPGE AMBP_HUMAN 173 6 -
GIPEDAIFTMPDRGECVPGE AMBP_BOVIN 173 6 -
GIPEDSIFTMANRGECIPGE O70160 173 6 -
GIPEDSIVMLPNNGECSPGE P70004 171 6 -