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PR01267

Identifier
GSTRNSFRASEM  [View Relations]  [View Alignment]  
Accession
PR01267
No. of Motifs
4
Creation Date
21-DEC-1999
Title
Mu-class glutathione S-transferase signature
Database References

PDB; 1GTU
SCOP; 1GSB
CATH; 1GTU
Literature References
1. ALLARDYCE, C.S., MCDONAGH, P.D., LIAN, L-Y., WOLF, R. AND ROBERTS, G.C.K.
The role of tyrosine-9 and the C-terminal helix in the catalytic mechanism
of alpha-class glutathione S-transferases.
BIOCHEM.J. 343 525-531 (1999).
 
2. NUCCETELLI, M.N., MAZZETTI, A.P., ROSSJOHN, J., PARKER, M.W., BOARD, P.,
CACCURI, A.M., FEDERICI, G., RICCI, G. AND LO BELLO, M.
Shifting substrate specificity of human glutathione transferase (from class
pi to class alpha) by a single point mutation.
BIOCHEM.BIOPHYS.RES.COMMUN. 252(1) 184-189 (1998).
 
3. DIRR, H., REINEMER, P. AND HUBER, R.
X-ray crystal structures of cytosolic glutathione S-transferases.
Implications for protein architecture, substrate recognition and catalytic
function.
EUR.J.BIOCHEMISTRY 220 645-661 (1994).
 
4. TAKAHASHI, Y., CAMBELL, E.A., HIRATA, Y., TAKAYAMA, T. AND LISTOWSKY, I.
A basis for differentiating among the multiple human mu-glutathione
S-transferases and molecular cloning of brain GSTM5.
J.BIOL.CHEM. 268(12) 8893-8 (1993).
 
5. HANSSON, L.O., BOLTON-GROB, R., MASSOUD, T. AND MANNERVIK, B.
Evolution of differential substrate specificities in mu class glutathione
transferases probed by DNA shuffling.
J.MOL.BIOL. 287 265-276 (1999).

Documentation
Glutathione S-transferases (GSTs) are a range of dimeric proteins that
catalyse the conjugation of glutathione to a wide range of hydrophobic
compounds through the formation of a thioether bond with their
electrophilic centre. Based on amino acid sequence identity, there are at
least seven major classes of GST (designated alpha, kappa, mu, pi, sigma, 
theta and zeta). Pi-, mu-, alpha- and theta-class crystal structures have
been elucidated; all possess a similar GSH-binding site (G subsite), but 
the hydrophobic substrate-binding site (H subsite) is subject to variation 
across the classes [1]. Whilst most of the GSTs share common substrates,
there are distinct differences in substrate preference between subfamilies.
Sequence similarity between classes is rather low, ranging between 20-30%.
However, a single point mutation in the H-subsite region is enough to shift
substrate specificity from class pi to alpha [2].
 
These enzymes have evolved as a cellular protection system against a range
of xenobiotics, oxidative metabolism by-products, and in particular are
known to metabolise a number of environmental carcinogens. The wide range
of GST isoforms present in the various subfamilies provides cells with an
efficient way of scavenging the huge number of potentially toxic compounds
encountered. Genetic differences in GST expression have been implicated in
individual susceptibility to certain types of cancer. Conversely, over- 
expression of GSTs is thought to be involved in the phenomenom of multi-drug
resistance to cancer chemotherapy.
 
In spite of relatively low sequence identity, the GSTs exhibit a high degree
of structural similarity. The structure comprises 2 domains: domain I is the
smaller of the two and is formed from the N-terminal region of the sequence
- it possesses an alpha/beta-type core structure comprising a central 
4-stranded beta-pleated sheet, flanked on one side by two alpha-helices and
on the other by a single helix; domain II is the larger of the domains and
occurs towards the C-terminal region of the sequence - it contains a
predominantly all-alpha-type core comprising 5 amphipathic alpha-helices,
arranged in a right-handed spiral. The active site is situated near the
subunit interface. G-subsite molecular recognition is attributable mostly 
to residues in domain I of one subunit and 1 or 2 residues in domain II of
the other subunit. Residues contributing to H-subsite specificity are found
within domains I and II of the same subunit [3].
 
At present, human mu-class GSTs can be subdivided into 5 isoforms based on
differing substrate specificities [4]. Mu-class GSTs are thought to be
involved in the detoxification of reactive oxygen species (cyclised
o-quinones) produced via oxidative metabolism of catecholamines. These
toxins are thought to be involved in neurological disorders of the
nigrostriatal and mesolimbic systems (Parkinsons and Schizophrenia,
respectively). Indeed, mu-class GSTs are expressed in the substantia nigra
and have preferential substrate specificity for the cyclised o-quinones
formed by catecholamine metabolism [5]. Mu-class GSTs possess the so-called
"mu-loop", which occurs between strand beta-2 and helix alpha-3. This is a
consequence of an insertion in the primary sequence and the loop allows the
overall domain I topology to remain [3].  
 
GSTRNSFRASEM is a 4-element fingerprint that provides a signature for mu-
class glutathione S-transferases. The fingerprint was derived from an
initial alignment of 12 sequences: the motifs were drawn from conserved 
regions spanning virtually the full alignment length - motif 1 includes the
C-terminal region of beta-strand 2 and the loop between strand 2 and 
alpha-helix 3; motif 2 spans helix 2 and the following loop; motif 3
includes the N-terminal region of helix 5; and motif 4 includes the 
C-terminal region of helix 6 and the following loop. Three iterations on 
SPTR37_10f were required to reach convergence, at which point a true set 
comprising 22 sequences was identified. Three partial matches were also 
found: GTM1_DERPT and O16058 are mu-class glutathione transferases from 
Dermatophagoides pteronyssinus (house-dust mite) and Echinococcus 
granulosus, respectively, which match motifs 1 and 2; and Q27653 is 
an unclassified GST that again matches motifs 1 and 2.
Summary Information
  22 codes involving  4 elements
0 codes involving 3 elements
3 codes involving 2 elements
Composite Feature Index
422222222
30000
23300
1234
True Positives
GTM1_HUMAN    GTM1_MOUSE    GTM1_RAT      GTM2_CHICK    
GTM2_HUMAN GTM2_MOUSE GTM2_RAT GTM3_HUMAN
GTM3_MOUSE GTM3_RAT GTM4_HUMAN GTM5_HUMAN
GTM5_MOUSE GTMU_CAVPO GTMU_CRILO GTMU_MESAU
GTMU_RABIT O35660 O60550 O97117
Q05465 Q9Z1B2
True Positive Partials
Codes involving 2 elements
GTM1_DERPT O16058 Q27653
Sequence Titles
GTM1_HUMAN  GLUTATHIONE S-TRANSFERASE MU 1 (EC 2.5.1.18) (GSTM1-1) (HB SUBUNIT 4) (GTH4) (GS 
GTM1_MOUSE GLUTATHIONE S-TRANSFERASE GT8.7 (EC 2.5.1.18) (GST 1-1) (GST CLASS- MU) - MUS MU
GTM1_RAT GLUTATHIONE S-TRANSFERASE YB1 (EC 2.5.1.18) (CHAIN 3) (GST M1-1) (GST CLASS-MU)
GTM2_CHICK GLUTATHIONE S-TRANSFERASE 2 (EC 2.5.1.18) (GST-CL2) (GST CLASS-MU) (GSTM1-1) - G
GTM2_HUMAN GLUTATHIONE S-TRANSFERASE MU 2 (EC 2.5.1.18) (GSTM2-2) (GST CLASS-MU) - HOMO SAP
GTM2_MOUSE GLUTATHIONE S-TRANSFERASE 5 (EC 2.5.1.18) (GST 5-5) (GST CLASS-MU) - MUS MUSCULU
GTM2_RAT GLUTATHIONE S-TRANSFERASE YB2 (EC 2.5.1.18) (CHAIN 4) (GST CLASS-MU) - RATTUS NO
GTM3_HUMAN GLUTATHIONE S-TRANSFERASE MU 3 (EC 2.5.1.18) (GSTM3-3) (GST CLASS-MU) - HOMO SAP
GTM3_MOUSE GLUTATHIONE S-TRANSFERASE GT9.3 (EC 2.5.1.18) (GST CLASS-MU) - MUS MUSCULUS (MOU
GTM3_RAT GLUTATHIONE S-TRANSFERASE YB3 (EC 2.5.1.18) (CHAIN 4) (GST CLASS-MU) - RATTUS NO
GTM4_HUMAN GLUTATHIONE S-TRANSFERASE MU 4 (EC 2.5.1.18) (GSTM4-4) (GTS-MU2) (GST CLASS-MU)
GTM5_HUMAN GLUTATHIONE S-TRANSFERASE MU 5 (EC 2.5.1.18) (GSTM5-5) (GST CLASS-MU) - HOMO SAP
GTM5_MOUSE GLUTATHIONE S-TRANSFERASE MU 5 (EC 2.5.1.18) (GSTM5-5) (GST CLASS-MU) (FIBROUS S
GTMU_CAVPO GLUTATHIONE S-TRANSFERASE B (EC 2.5.1.18) (GST B) (GST CLASS-MU) - CAVIA PORCELL
GTMU_CRILO GLUTATHIONE S-TRANSFERASE Y1 (EC 2.5.1.18) (CHAIN 3) (GST CLASS-MU) - CRICETULUS
GTMU_MESAU GLUTATHIONE S-TRANSFERASE (EC 2.5.1.18) (GST CLASS-MU) - MESOCRICETUS AURATUS (G
GTMU_RABIT GLUTATHIONE S-TRANSFERASE MU 1 (EC 2.5.1.18) (GST MU I) (GST CLASS- MU) - ORYCTO
O35660 GLUTATHIONE-S-TRANSFERASE CLASS M5 (EC 2.5.1.18) (GLUTATHIONE TRANSFERASE) (GLUT
O60550 GLUTATHIONE S-TRANSFERASE MU 3 - HOMO SAPIENS (HUMAN).
O97117 GLUTATHIONE S-TRANSFERASE - BOOPHILUS MICROPLUS (CATTLE TICK).
Q05465 GLUTATHIONE S-TRANSFERASE (EC 2.5.1.18) (CLASS-MU) - HOMO SAPIENS (HUMAN).
Q9Z1B2 GLUTATHIONE S-TRANSFERASE M5 (EC 2.5.1.18) - RATTUS NORVEGICUS (RAT).

GTM1_DERPT GLUTATHIONE S-TRANSFERASE (EC 2.5.1.18) (GST CLASS-MU) (MAJOR ALLERGEN P DP 15)
O16058 GLUTATHIONE S-TRANSFERASE - ECHINOCOCCUS GRANULOSUS.
Q27653 GLUTATHIONE TRANSFERASE (EC 2.5.1.18) (GLUTATHIONE S-ALKYLTRANSFERASE) (GLUTATHI
Scan History
SPTR37_10f 3  90   NSINGLE    
Initial Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
KKYTMGDAPDYDR GTM5_HUMAN 30 30 -
KRYTMGDAPDFDR GTM3_RAT 30 30 -
KKYTMGDAPDYDR GTM1_HUMAN 30 30 -
KKYTMGDAPDYDR GTM4_HUMAN 31 31 -
KKYTMGDAPDYDR GTM2_MOUSE 30 30 -
KRYAMGDAPDYDR GTM1_RAT 30 30 -
KKYSMGDAPDYDR GTM2_RAT 30 30 -
KRYTMGDAPDFDR GTM1_MOUSE 30 30 -
KRYVMGDAPNFDR GTM3_MOUSE 30 30 -
KKYTMGDAPDYDR GTM2_HUMAN 30 30 -
KRYTCGEAPDYDR GTM3_HUMAN 35 35 -
KRYICGEAPDYDR GTM5_MOUSE 34 34 -

Motif 2 width=13
Element Seqn Id St Int Rpt
SQWLNEKFKLGLD GTM5_HUMAN 43 0 -
SQWLNEKFKLGLD GTM3_RAT 43 0 -
SQWLNEKFKLGLD GTM1_HUMAN 43 0 -
SQWLNEKFKLGLD GTM4_HUMAN 44 0 -
SQWLSEKFKLGLD GTM2_MOUSE 43 0 -
SQWLNEKFKLGLD GTM1_RAT 43 0 -
SQWLSEKFKLGLD GTM2_RAT 43 0 -
SQWLNEKFKLGLD GTM1_MOUSE 43 0 -
SQWLSEKFNLGLD GTM3_MOUSE 43 0 -
SQWLNEKFKLGLD GTM2_HUMAN 43 0 -
SQWLDVKFKLDLD GTM3_HUMAN 48 0 -
SQWLDVKFKLDLD GTM5_MOUSE 47 0 -

Motif 3 width=12
Element Seqn Id St Int Rpt
CGETEEEKIRVD GTM5_HUMAN 86 30 -
CGETEEERIRVD GTM3_RAT 86 30 -
CGETEEEKIRVD GTM1_HUMAN 86 30 -
CGETEEEKIRVD GTM4_HUMAN 87 30 -
CGETEEERIRVD GTM2_MOUSE 86 30 -
CGETEEERIRAD GTM1_RAT 86 30 -
CGETEEERIRVD GTM2_RAT 86 30 -
DGETEEERIRAD GTM1_MOUSE 86 30 -
CGETEEERIRVD GTM3_MOUSE 86 30 -
CGESEKEQIRED GTM2_HUMAN 86 30 -
CGETEEEKIRVD GTM3_HUMAN 91 30 -
CGDTEEEKIRVD GTM5_MOUSE 90 30 -

Motif 4 width=14
Element Seqn Id St Int Rpt
SEFLGKRPWFAGDK GTM5_HUMAN 138 40 -
SEFLGKRPWFAGDK GTM3_RAT 138 40 -
SEFLGKRPWFAGNK GTM1_HUMAN 138 40 -
SQFLGKRPWFVGDK GTM4_HUMAN 139 40 -
SEFLGKQPWFAGNK GTM2_MOUSE 138 40 -
SEFLGKRPWFAGDK GTM1_RAT 138 40 -
SEFLGKQPWFAGNK GTM2_RAT 138 40 -
SEFLGKRPWFAGDK GTM1_MOUSE 138 40 -
SEFLGKRPWFAGDK GTM3_MOUSE 138 40 -
SQFLGKQPWFLGDK GTM2_HUMAN 138 40 -
SMFLWKFSWFAGEK GTM3_HUMAN 143 40 -
SLFLGKFTWFAGEK GTM5_MOUSE 142 40 -
Final Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
KKYTMGDAPDYDR GTM5_HUMAN 30 30 -
KRYTMGDAPDFDR GTM3_RAT 30 30 -
KKYTMGDAPDYDR GTM1_HUMAN 30 30 -
KKYTMGDAPDSDR GTMU_CRILO 30 30 -
KKYTMGDAPDYDR GTM4_HUMAN 31 31 -
KKYTMGDAPDYDR Q05465 31 31 -
KKYTMGDAPDYDR GTM2_MOUSE 30 30 -
KRYAMGDAPDYDR GTM1_RAT 30 30 -
KKYSMGDAPDYDR GTM2_RAT 30 30 -
KRYTMGDAPDFDR GTM1_MOUSE 30 30 -
KRYVMGDAPNFDR GTM3_MOUSE 30 30 -
RRYAMGDAPDYDR O35660 31 31 -
KKYTMGDAPNFDR GTMU_MESAU 30 30 -
KRYNMGDAPDYDR GTMU_CAVPO 30 30 -
KRYTCGEAPDYDR O60550 35 35 -
KKYTMGDAPDYDR GTM2_HUMAN 30 30 -
KRYTCGEAPDYDR GTM3_HUMAN 35 35 -
KKYTMGDAPNYDQ GTMU_RABIT 30 30 -
KQYTCGEAPDYDR Q9Z1B2 35 35 -
KRYICGEAPDYDR GTM5_MOUSE 34 34 -
RRYKAGPAPDFDP GTM2_CHICK 30 30 -
KRYTCGPPPDFDR O97117 31 31 -

Motif 2 width=13
Element Seqn Id St Int Rpt
SQWLNEKFKLGLD GTM5_HUMAN 43 0 -
SQWLNEKFKLGLD GTM3_RAT 43 0 -
SQWLNEKFKLGLD GTM1_HUMAN 43 0 -
SQWLNEKFKLGLD GTMU_CRILO 43 0 -
SQWLNEKFKLGLD GTM4_HUMAN 44 0 -
SQWLNEKFKLGLD Q05465 44 0 -
SQWLSEKFKLGLD GTM2_MOUSE 43 0 -
SQWLNEKFKLGLD GTM1_RAT 43 0 -
SQWLSEKFKLGLD GTM2_RAT 43 0 -
SQWLNEKFKLGLD GTM1_MOUSE 43 0 -
SQWLSEKFNLGLD GTM3_MOUSE 43 0 -
SQWLNDKFKLXLD O35660 44 0 -
SQWLNEKFKLGLD GTMU_MESAU 43 0 -
SQWLNEKFKLGLD GTMU_CAVPO 43 0 -
SQWLDVKFKLDLD O60550 48 0 -
SQWLNEKFKLGLD GTM2_HUMAN 43 0 -
SQWLDVKFKLDLD GTM3_HUMAN 48 0 -
SKWLSEKFTLGLD GTMU_RABIT 43 0 -
SQWLDVKFKLDLD Q9Z1B2 48 0 -
SQWLDVKFKLDLD GTM5_MOUSE 47 0 -
SDWTNEKEKLGLD GTM2_CHICK 43 0 -
SSWLNEKTKLGLE O97117 44 0 -

Motif 3 width=12
Element Seqn Id St Int Rpt
CGETEEEKIRVD GTM5_HUMAN 86 30 -
CGETEEERIRVD GTM3_RAT 86 30 -
CGETEEEKIRVD GTM1_HUMAN 86 30 -
CGETEEERIRVD GTMU_CRILO 86 30 -
CGETEEEKIRVD GTM4_HUMAN 87 30 -
CGETEEEKIRVD Q05465 87 30 -
CGETEEERIRVD GTM2_MOUSE 86 30 -
CGETEEERIRAD GTM1_RAT 86 30 -
CGETEEERIRVD GTM2_RAT 86 30 -
DGETEEERIRAD GTM1_MOUSE 86 30 -
CGETEEERIRVD GTM3_MOUSE 86 30 -
CGETEEERIRVD O35660 87 30 -
CGETEEERIQLD GTMU_MESAU 86 30 -
CGVTEEETIRMD GTMU_CAVPO 86 30 -
CGETEEEKIRVD O60550 91 30 -
CGESEKEQIRED GTM2_HUMAN 86 30 -
CGETEEEKIRVD GTM3_HUMAN 91 30 -
CGETEEERIRVD GTMU_RABIT 86 30 -
CGDTEEEKIRVD Q9Z1B2 91 30 -
CGDTEEEKIRVD GTM5_MOUSE 90 30 -
CGETEVEKQRVD GTM2_CHICK 86 30 -
EGKTEAEKQRVD O97117 87 30 -

Motif 4 width=14
Element Seqn Id St Int Rpt
SEFLGKRPWFAGDK GTM5_HUMAN 138 40 -
SEFLGKRPWFAGDK GTM3_RAT 138 40 -
SEFLGKRPWFAGNK GTM1_HUMAN 138 40 -
SEFLGKRPWFAGDK GTMU_CRILO 138 40 -
SQFLGKRPWFVGDK GTM4_HUMAN 139 40 -
SQFLGKRPWFVGDK Q05465 139 40 -
SEFLGKQPWFAGNK GTM2_MOUSE 138 40 -
SEFLGKRPWFAGDK GTM1_RAT 138 40 -
SEFLGKQPWFAGNK GTM2_RAT 138 40 -
SEFLGKRPWFAGDK GTM1_MOUSE 138 40 -
SEFLGKRPWFAGDK GTM3_MOUSE 138 40 -
SEFLGKQPWFAGDK O35660 139 40 -
SEFLGKRSWFAGDK GTMU_MESAU 138 40 -
SQFLGKLPWFAGNK GTMU_CAVPO 138 40 -
SMFLGKFSWFAGEK O60550 143 40 -
SQFLGKQPWFLGDK GTM2_HUMAN 138 40 -
SMFLWKFSWFAGEK GTM3_HUMAN 143 40 -
SQFLGSLPWFAGDK GTMU_RABIT 138 40 -
SLFLGKFTWFAGEK Q9Z1B2 143 40 -
SLFLGKFTWFAGEK GTM5_MOUSE 142 40 -
SRFLGSRSWFVGDK GTM2_CHICK 138 40 -
SDYLGTHKFFAGDN O97117 139 40 -