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PR01193

Identifier
GLUCTRSPORT4  [View Relations]  [View Alignment]  
Accession
PR01193
No. of Motifs
4
Creation Date
15-APR-1999
Title
Glucose transporter type 4 (GLUT4) signature
Database References
PRINTS; PR00171 SUGRTRNSPORT; PR00172 GLUCTRNSPORT
PRODOM; PD015687
INTERPRO; IPR002441
Literature References
1. GOULD, G.W. AND BELL, G.I.
Facilitative glucose transporters: an expanding family.
TRENDS BIOCHEM.SCI. 15 18-23 (1990).
 
2. BELL, G.I., BURANT, C.F., TAKEDA, J. AND GOULD, G.W.
Structure and function of mammalian facilitative sugar transporters.
J.BIOL.CHEM. 268 19161-19164 (1993).
 
3. MUECKLER, M.
Facilitative glucose transporters.
EUR.J.BIOCHEMISTRY 219 713-725 (1994).
 
4. KAYANO, T., BURANT, C.F., FUKUMOTO, H., GOULD, G.W., FAN, Y.S.,
EDDY, R.L., BYERS, M.G., SHOWS, T.B., SEINO, S. AND BELL, G.I.
Human facilitative glucose transporters. Isolation, functional
characterization, and gene localization of cDNAs encoding an isoform
and an unusual glucose transporter pseudogene-like sequence (GLUT6).
J.BIOL.CHEM. 265 13278-13282 (1990).
 
5. BURCHELL, A.
A re-evaluation of GLUT 7.
BIOCHEMISTRY J. 331 973 (1998).
 
6. MAIDEN, M.C.J., DAVIS, E.O., BALDWIN, S.A., MOORE, D.C.M. AND
HENDERSON, P.J.F.
Mammalian and bacterial sugar transport proteins are homologous.
NATURE 325 641-643 (1987).
 
7. MARGER, M.D. AND SAIER, M.H., JR.
A major superfamily of transmembrane facilitators that catalyse uniport,
symport and antiport.
TRENDS BIOCHEM.SCI. 18 13-20 (1993).
 
8. HEDIGER, M.A., COADY, M.J., IKEDA, T.S. AND WRIGHT, E.M.
Expression cloning and cDNA sequencing of the Na+/glucose co-transporter.
NATURE 330 379-381 (1987).

Documentation
The ability to transport glucose across the plasma membrane is a feature
common to nearly all cells, from simple bacteria through to highly
specialised mammalian neurones. Facilitative glucose (and fructose)
transport is mediated by members of the GLUT transporter family. These
are glycosylated transmembrane (TM) proteins that transport glucose in a
passive (i.e., energy-independent) manner. In consequence, they can only
transport glucose down its concentration gradient. Currently, five such
mammalian transporters have been cloned and functionally characterised
[1-3]. Four of these transport glucose (GLUT1-4), whereas GLUT5 prefer-
entially transports fructose. A sixth cDNA, encoding an apparent glucose
transporter, was cloned but was found to be a pseudo-gene (GLUT6) [4].
Similarly, another cDNA thought to encode a glucose transporter that was
targeted to the endoplasmic reticulum was eventually realised to be an
experimental cloning artefact (GLUT7) [5].
 
The five confirmed isoforms are expressed in a tissue and cell-specific
manner, and have been found to exhibit distinct kinetic and regulatory
properties, presumably reflecting their specific functional roles in these
locations. Hydropathy analysis reveals they have 12 presumed TM domains, 
and that they belong to a much larger `major facilitator superfamily' of 12
TM transporters that are involved in the transport of a variety of hexoses
and other carbon compounds, including: bacterial sugar-proton symporters 
(H+/xylose and H+/arabinose); bacterial transporters of carboxylic acids
and antibiotics; and sugar transporters in various yeast, protozoa and
higher plants. Nevertheless, amino acid identity within the superfamily may
be as low as ~25% [6,7]. Besides the 12 presumed TM domains, the most
characteristic structural feature of the superfamily is the presence of a
five residue motif (RXGRR, where X is any amino acid). In the GLUT 
transporters, this motif is present in the presumed cytoplasmic loops
connecting TM domains 2 with 3, and also 8 with 9. The 12 TM transporter
superfamily appears to be structurally unrelated to the Na+-coupled,
Na+/glucose co-transporters (SGLT1-3) found in the intestine and kidney,
which are able to transport glucose against its concentration gradient [8].
 
Comparison of the hydropathy profiles for GLUT1-5 reveals that they are
virtually superimposable, despite the fact that their primary structures
may differ by up to 60%. Of the presumed TM domains, the fourth, fifth
and sixth are the most highly conserved, and conserved residues are also
found in the short exofacial loops joining the putative TM regions. The
presumed cytoplasmic N- and C-termini, and the extracellular loop between
the first and second TM domains, show the greatest divergence, both in
terms of primary structure and size.
 
GLUT4 is thought to be an insulin-responsive glucose transporter. It is
expressed only in skeletal muscle, heart and adipocytes. These tissues
are insulin-sensitive in that they respond to increased blood insulin
levels by a rapid and reversible 20-30 fold increase in glucose transport.
This is thought to be brought about (at least partially) by the trans-
location of a latent pool of glucose transporters from an intracellular
site to the plasma membrane. Indeed, GLUT4 is found predominantly in
intracellular membranes in these cell types when unstimulated by insulin.
It consists of 509 amino acids (human isoform) and shows ~60% amino acid
identity to the GLUT1-3 isoforms, being most similar to GLUT1. The
mechanism of its intracellular targeting remains to be resolved, with
both N- and C-terminal portions of the molecule having been reported to be
involved in the targeting (3).
 
GLUCTRSPORT4 is a 4-element fingerprint that provides a signature for the
mammalian glucose transporter type 4 isoform. The fingerprint was derived
from an initial alignment of 4 sequences: the motifs were drawn from
conserved regions spanning virtually the full alignment length, focusing on
those sections that characterise the glucose co-transporter type 4 isoform
but distinguish it from others - motifs 1 and 2 lie on the first putative
extracellular loop, located between the first two presumed TM domains; and
motifs 3 and 4 encode the final 24 residues of the presumed cytoplasmic
C-terminus. A single iteration on SPTR37_9f was required to reach 
convergence, no further sequences being identified beyond the starting set.
Summary Information
4 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
44444
30000
20000
1234
True Positives
GTR4_BOVIN    GTR4_HUMAN    GTR4_MOUSE    GTR4_RAT      
Sequence Titles
GTR4_BOVIN  GLUCOSE TRANSPORTER TYPE 4, INSULIN-RESPONSIVE - BOS TAURUS (BOVINE). 
GTR4_HUMAN GLUCOSE TRANSPORTER TYPE 4, INSULIN-RESPONSIVE - HOMO SAPIENS (HUMAN).
GTR4_MOUSE GLUCOSE TRANSPORTER TYPE 4, INSULIN-RESPONSIVE (GT2) - MUS MUSCULUS (MOUSE).
GTR4_RAT GLUCOSE TRANSPORTER TYPE 4, INSULIN-RESPONSIVE - RATTUS NORVEGICUS (RAT).
Scan History
SPTR37_9f  1  150  NSINGLE    
Initial Motifs
Motif 1  width=9
Element Seqn Id St Int Rpt
QSYNATWLG GTR4_MOUSE 56 56 -
QSYNATWLG GTR4_RAT 54 54 -
QSYNETWLG GTR4_HUMAN 54 54 -
QSYNETWLG GTR4_BOVIN 54 54 -

Motif 2 width=13
Element Seqn Id St Int Rpt
QGPGGPDSIPQGT GTR4_MOUSE 66 1 -
QGPGGPDSIPQGT GTR4_RAT 64 1 -
QGPEGPSSIPPGT GTR4_HUMAN 64 1 -
QGPEGPGSIPPGT GTR4_BOVIN 64 1 -

Motif 3 width=13
Element Seqn Id St Int Rpt
TPSLLEQEVKPST GTR4_MOUSE 487 408 -
TPSLLEQEVKPST GTR4_RAT 486 409 -
TPSLLEQEVKPST GTR4_HUMAN 486 409 -
TPSLLEQEVKPST GTR4_BOVIN 486 409 -

Motif 4 width=11
Element Seqn Id St Int Rpt
ELEYLGPDEND GTR4_MOUSE 500 0 -
ELEYLGPDEND GTR4_RAT 499 0 -
ELEYLGPDEND GTR4_HUMAN 499 0 -
ELEYLGPDEHD GTR4_BOVIN 499 0 -
Final Motifs
Motif 1  width=9
Element Seqn Id St Int Rpt
QSYNATWLG GTR4_MOUSE 56 56 -
QSYNATWLG GTR4_RAT 54 54 -
QSYNETWLG GTR4_HUMAN 54 54 -
QSYNETWLG GTR4_BOVIN 54 54 -

Motif 2 width=13
Element Seqn Id St Int Rpt
QGPGGPDSIPQGT GTR4_MOUSE 66 1 -
QGPGGPDSIPQGT GTR4_RAT 64 1 -
QGPEGPSSIPPGT GTR4_HUMAN 64 1 -
QGPEGPGSIPPGT GTR4_BOVIN 64 1 -

Motif 3 width=13
Element Seqn Id St Int Rpt
TPSLLEQEVKPST GTR4_MOUSE 487 408 -
TPSLLEQEVKPST GTR4_RAT 486 409 -
TPSLLEQEVKPST GTR4_HUMAN 486 409 -
TPSLLEQEVKPST GTR4_BOVIN 486 409 -

Motif 4 width=11
Element Seqn Id St Int Rpt
ELEYLGPDEND GTR4_MOUSE 500 0 -
ELEYLGPDEND GTR4_RAT 499 0 -
ELEYLGPDEND GTR4_HUMAN 499 0 -
ELEYLGPDEHD GTR4_BOVIN 499 0 -