The Classical PTPs

In the classical PTPs the signature motif is contained within a conserved catalytic domain of 280 residues, which is flanked on either the N- or C-terminal side by noncatalytic sequences that serve a regulatory function. Similarities in the catalytic domain sequence, which coincide with similarities in the structural and functional domains present in the regulatory segments, allow the PTPs to be grouped into 17 subtypes, including receptor-like and nontransmembrane categories (Fig. 1) [2].

The specificity of the enzymes for phosphotyrosyl residues is explained in part by the depth of the active site cleft. This is defined by a tyrosyl residue (Y46 in PTP1B), which forms one side of the cleft [13]. Thus, a pTyr residue in a substrate is of sufficient length to gain access to the nucleophilic Cys at the base of the active site cleft, whereas pSer and pThr residues would be too short to be dephos-phorylated. Recently, a search of cDNA sequences in the GenBank database revealed the existence of 113 such PTPs in vertebrates, including 37 in humans [2]. Additional mining of the human genome sequence increased the number of classical PTPs to 38 and identified 12 pseudogenes (see Chapter 109

Nontransmembrane PTP subtypes (NT)

Receptor-like PTP subtypes (R)

R2A R3

R1/R6

NT2 NT3 NT4 NT5 NT6 NT7 NT8 NT9

R1/R6

NT2 NT3 NT4 NT5 NT6 NT7 NT8 NT9

PTPß DEP1 SAP1 GLEPP1 PTPS31

PTP|i LAR PTPa PTPy

PTPk PTPa PTPe PTPÇ

PTPp PTP5 PTPX

PCPTP1 HePTP STEP

PTP1B TCPTP

BDP1 PEST LyPTP

PTPD1 PTPD2

PTP BAS

PTP domain

Fibronectin III like repeat

PTPß DEP1 SAP1 GLEPP1 PTPS31

PTP|i LAR PTPa PTPy

PTPk PTPa PTPe PTPÇ

PTPp PTP5 PTPX

PCPTP1 HePTP STEP

PTP1B TCPTP

BDP1 PEST LyPTP

PTPD1 PTPD2

PTP BAS

PTP domain

PEST-like

FERM domain

Cellular retinalde hyde binding protein-like

BRO-1 Homology

[hd His-domain o

PDZ domain MePin/A5/|

Src homology

Cj domain

. OSTPTP Immuno-

globulin-like

Fibronectin III like repeat

Carbonic anhydrase-like

RDGS adhesion recognition motif

Q Cadherin-like

Heavily ^ glycosylated

Figure 1 Schematic representation of PTP family members. The PTPs have been classified into nine non-transmembrane (NT) and eight receptor-like (R) subtypes based on sequence similarity. Only the human PTPs are listed, and a representative of each subtype is shown. (From Andersen, J. N. et al., Mol. Cell. Biol. 21, 7117-7136, 2001. With permission.)

and Andersen et al. submitted). To provide a framework for a genome-wide analysis of the PTPs we have compiled a comprehensive online resource for sequence analysis of the pTyr-specific members of the PTP family. The website includes amino acid sequence alignments, phylogenetic classification of family members, and evaluation of amino acid conservation in three dimensions using X-ray crystal structures of PTP domains and low-resolution homology modeling. The PTP database is available online at http: //ptp.cshl.edu or http: //science.novonordisk.com/ptp. In the future, we plan to expand this resource to include pseudogenes, intron/exon organization, and splice variants as well as mutations, polymorphisms, and disease linkages.

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