******************************************************
* Tyrosine specific protein phosphatases active site *
******************************************************

Tyrosine specific protein phosphatases  (EC 3.1.3.48)  (PTPase) [1 to 5]   are
enzymes  that catalyze the removal of a phosphate group attached to a tyrosine
residue.  These  enzymes  are  very  important in  the control of cell growth,
proliferation, differentiation and transformation.   Multiple  forms of PTPase
have been characterized  and   can be  classified into two categories: soluble
PTPases and transmembrane receptor proteins that contain PTPase domain(s). The
currently known PTPases are listed below:

Soluble PTPases.

 - PTPN3  (H1)  and PTPN4  (MEG), enzymes that contain an N-terminal band 4.1-
   like  domain (see the relevant section) and could act at junctions  between
   the membrane and cytoskeleton.
 - PTPN6  (PTP-1C  or HCP or SHP) and PTPN11, enzymes which contain two copies
   of the  SH2  domain  at  its  N-terminal extremity.  The Drosophila protein
   corkscrew (gene csw) also belongs to this subgroup.
 - PTPN7 (CL100 or 3CH134), which could play  an important regulatory role  in
   the  cellular  response  to  adverse environmental   challenges,  including
   oxidants and hyperthermia.
 - PTPN1 (PTP-1B).
 - PTPN2 (T-cell PTPase; TC-PTP).
 - PTPN5 (STEP).
 - PTP-G1.
 - Nuclear PAC-1.

 - Yeast CDC14 which may be involved in chromosome segregation.
 - Yeast PTP1.
 - Yeast PTP2  which  may  be  involved    in  the  ubiquitin-mediated protein
   degradation pathway.
 - Yeast YVH1.
 - Fission  yeast  pyp1  and pyp2 which play a role in inhibiting the onset of
   mitosis.
 - Fission yeast pyp3 which contributes to the dephosphorylation of cdc2.
 - Yersinia virulence plasmid PTPAses (gene yopH).
 - Vaccinia virus H1 PTPase.
 - Autographa californica nuclear polyhedrosis virus 19 Kd PTPase.

Receptor PTPases.

Structurally, all known receptor PTPases, are  made  up  of  a variable length
extracellular domain,  followed    by a  transmembrane region and a C-terminal
catalytic cytoplasmic domain. Some of the receptor PTPases contain fibronectin
type III   (FN-III)  repeats,  immunoglobulin-like  domains,  MAM  domains  or
carbonic anhydrase-like domains in their extracellular region. The cytoplasmic
region generally  contains two copies of the PTPAse domain. The first seems to
have enzymatic    activity,  while  the second is inactive but seems to affect
substrate specificity  of  the first. In these domains, the catalytic cysteine
is generally conserved but some other, presumably important, residues are not.

In the  following  table,  the  domain  structure of known receptor PTPases is
shown:

                                        Extracellular         Intracellular
                                        -------------------   -------------
                                        Ig  FN-3   CAH  MAM   PTPase

Leukocyte common antigen (LCA) (CD45)    0     0     0    0      2
Leukocyte antigen related (LAR)          3     8     0    0      2
Drosophila DLAR                          3     9     0    0      2
Drosophila DPTP                          2     2     0    0      2
PTP-alpha (LRP)                          0     0     0    0      2
PTP-beta                                 0    16     0    0      1
PTP-gamma                                0     1     1    0      2
PTP-delta                                0    >7     0    0      2
PTP-epsilon                              0     0     0    0      2
PTP-kappa                                1     4     0    1      2
PTP-mu                                   1     4     0    1      2
PTP-zeta                                 0     1     1    0      2

PTPase  domains  consist  of about 300  amino  acids.  There are two conserved
cysteines, the  second  one  has  been  shown  to  be  absolutely required for
activity. Furthermore,  a  number  of  conserved  residues  in  its  immediate
vicinity have also been shown to be important.

We derived  a signature pattern for PTPase domains centered on the active site
cysteine.

-Consensus pattern: [LIVM]-H-C-x(2)-G-x(3)-[STC]-[STAG]-x-[LIVMFY]
                    [C is the active site residue]
-Sequences known to belong to this class detected by the pattern: ALL,  except
 for rat PTPN5 and yeast YVH1.
-Other sequence(s) detected in SWISS-PROT: a  putative  helicase  from  potato
 virus M, a hypothetical 12 Kd  protein  from the avirulence AVRSB1 region  of
 Xanthomonas campestris.

-Note: the M-phase inducer phosphatases (cdc25-type phosphatase) are tyrosine-
 protein phosphatases which, while structurally related to other PTPases,  are
 divergent enough to justify a separate entry.

-Last update: June 1994 / Pattern and text revised.

[ 1] Fischer E.H., Charbonneau H., Tonks N.K.
     Science 253:401-406(1991).
[ 2] Charbonneau H., Tonks N.K.
     Annu. Rev. Cell Biol. 8:463-493(1992).
[ 3] Trowbridge I.S.
     J. Biol. Chem. 266:23517-23520(1991).
[ 4] Tonks N.K., Charbonneau H.
     Trends Biochem. Sci. 14:497-500(1989).
[ 5] Hunter T.
     Cell 58:1013-1016(1989).