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Review
. 2001 Nov;21(21):7117-36.
doi: 10.1128/MCB.21.21.7117-7136.2001.

Structural and evolutionary relationships among protein tyrosine phosphatase domains

J N Andersen  1 , O H Mortensen, G H Peters, P G Drake, L F Iversen, O H Olsen, P G Jansen, H S Andersen, N K Tonks, N P Møller
Affiliations
Review

Structural and evolutionary relationships among protein tyrosine phosphatase domains

J N Andersen et al. Mol Cell Biol. 2001 Nov.
No abstract available

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Figures

FIG. 1
FIG. 1
Sequence comparison of human PTP domains. Shown is an amino acid sequence alignment of 37 human PTP domains (from nontransmembrane PTP and RPTP domains D1) (above) and comparison with domain D2 sequences of RPTPs (below). Amino acids are numbered according to the residue position in human PTP1B. The locations of α-helices and β-strands (based on the X-ray crystal structure of PTP1B [7]) are shown at the top of the alignment. Twenty-two invariant residues (underscored) and 42 highly conserved residues (>80% identity) are indicated at the bottom of the alignment. The PTP consensus motifs (M1 to M10) are detailed in Table 2. Amino acids are color coded according to their degree of conservation, as indicated below the alignment. Nonconserved residues involved in the definition of substrate selectivity-determining regions are boxed with black lines (see text and Fig. 9). The four-residue conserved linker in tandem RPTP enzymes is boxed in yellow (above) and corresponds to encircled area 1 in Fig. 8. Sequences were aligned using the Clustalw algorithm and the Genetics Computer Group PileUp software (version 8.1) by applying the BLOSUM 62 scoring matrix together with default gap creation and extension penalty. Alignment of the N termini of the PTP domains was guided by crystallographic structural data and secondary structure predictions (nnpredict at http://www.cmpharm.ucsf.edu). The complete alignment of all vertebrate PTP domains can be retrieved (http://science.novonordisk.com/ptp) in several standard GCG formats, including MSF, TFA, and ALN.
FIG. 1
FIG. 1
Sequence comparison of human PTP domains. Shown is an amino acid sequence alignment of 37 human PTP domains (from nontransmembrane PTP and RPTP domains D1) (above) and comparison with domain D2 sequences of RPTPs (below). Amino acids are numbered according to the residue position in human PTP1B. The locations of α-helices and β-strands (based on the X-ray crystal structure of PTP1B [7]) are shown at the top of the alignment. Twenty-two invariant residues (underscored) and 42 highly conserved residues (>80% identity) are indicated at the bottom of the alignment. The PTP consensus motifs (M1 to M10) are detailed in Table 2. Amino acids are color coded according to their degree of conservation, as indicated below the alignment. Nonconserved residues involved in the definition of substrate selectivity-determining regions are boxed with black lines (see text and Fig. 9). The four-residue conserved linker in tandem RPTP enzymes is boxed in yellow (above) and corresponds to encircled area 1 in Fig. 8. Sequences were aligned using the Clustalw algorithm and the Genetics Computer Group PileUp software (version 8.1) by applying the BLOSUM 62 scoring matrix together with default gap creation and extension penalty. Alignment of the N termini of the PTP domains was guided by crystallographic structural data and secondary structure predictions (nnpredict at http://www.cmpharm.ucsf.edu). The complete alignment of all vertebrate PTP domains can be retrieved (http://science.novonordisk.com/ptp) in several standard GCG formats, including MSF, TFA, and ALN.
FIG. 1
FIG. 1
Sequence comparison of human PTP domains. Shown is an amino acid sequence alignment of 37 human PTP domains (from nontransmembrane PTP and RPTP domains D1) (above) and comparison with domain D2 sequences of RPTPs (below). Amino acids are numbered according to the residue position in human PTP1B. The locations of α-helices and β-strands (based on the X-ray crystal structure of PTP1B [7]) are shown at the top of the alignment. Twenty-two invariant residues (underscored) and 42 highly conserved residues (>80% identity) are indicated at the bottom of the alignment. The PTP consensus motifs (M1 to M10) are detailed in Table 2. Amino acids are color coded according to their degree of conservation, as indicated below the alignment. Nonconserved residues involved in the definition of substrate selectivity-determining regions are boxed with black lines (see text and Fig. 9). The four-residue conserved linker in tandem RPTP enzymes is boxed in yellow (above) and corresponds to encircled area 1 in Fig. 8. Sequences were aligned using the Clustalw algorithm and the Genetics Computer Group PileUp software (version 8.1) by applying the BLOSUM 62 scoring matrix together with default gap creation and extension penalty. Alignment of the N termini of the PTP domains was guided by crystallographic structural data and secondary structure predictions (nnpredict at http://www.cmpharm.ucsf.edu). The complete alignment of all vertebrate PTP domains can be retrieved (http://science.novonordisk.com/ptp) in several standard GCG formats, including MSF, TFA, and ALN.
FIG. 2
FIG. 2
Classification of family of PTPs into 17 subtypes. Shown is an unrooted tree derived from the alignment of 113 vertebrate PTP domain sequences (residue positions 1 to 279 in human PTP1B). The tree was drawn by the neighbor-joining method (73). The horizontal distance indicates the degree of sequence divergence, and the scale at the top corner represents the number of substitution events (10 per 100 amino acids). Seventeen PTP domain subtypes were identified from the phylogram: nine nontransmembrane subtypes (NT1 to NT9), five tandem receptor-like subtypes (R1/R6, R2A, R2B, R4, and R5), and three single-domain RPTP subtypes (R3, R7, and R8 [subtype R8 is believed to be catalytically inactive]). As a statistical test of the significance of sequence similarity within PTP subtypes, bootstrap values were calculated (values are at the dendogram node). With the exception of the RPTPβ-like subtype (R3) and the tandem PTP domain supertype, all subdivisions were assigned based on maximal bootstrap values (1,000). (A tree including the PTP domain D2 sequences can be viewed [http://science.novonordisk.com/ptp], and the raw data files can also be retrieved in several standard GCG formats).
FIG. 3
FIG. 3
Schematic representation of PTP family members. Determination of sequence similarity among PTP catalytic domains (Fig. 2) was used to classify the PTP family of enzymes into nine nontransmembrane PTP subtypes (NT) and eight RPTP subtypes (R). Only the human PTPs are listed, and a representative member of each subtype is shown. Synonyms and classifications of all vertebrate PTPs are given in Table 1. PTPs having closely related catalytic domains also tend to be similar in overall structural topology.
FIG. 4
FIG. 4
Crystal structures of vertebrate PTP domains show conserved fold and consistent Cα-backbone trace. PTP1B (magenta), RPTPα (gray), RPTPμ (red), LAR (blue), SHP1 (green), and SHP2 (yellow) were aligned and superimposed using Quanta (Molecular Simulations Inc.). For clarity, residues 280 to 298 (C terminal) of PTP1B, 250 to 281 (N terminal) and 522 to 532 (C terminal) of SHP1, and 2 to 218 (N terminal) of SHP2 were omitted from the figure, as well as D2 of LAR. The calculated RMS deviations between all Cα atoms between PTP1B and other PTPs are as follows: PTPα, 1.35 Å; RPTPμ, 2.72 Å; LAR D1, 2.78 Å; SHP1, 3.14 Å; and SHP2, 2.74 Å. For comparison, the RMS deviation between domains D1 and D2 of LAR is 1.3 Å. The X-ray structures are compared in their native open conformation.
FIG. 5
FIG. 5
The HCSAGXGR and IAXQGP motifs reside within the most highly conserved microenvironment of the PTP structure. Residues located within a highly conserved three dimensional space of the PTP structure are identified by peaks. The Cα-regiovariation score was calculated using the alignment information in Fig. 1 and the tertiary structure of PTP1B as template. Neighboring residues were defined using a three-dimensional 7-Å sphere of influence. Similar results were obtained for a 5- to 8-Å sphere and when using PTPα, PTPμ, or SHP2 as templates for Cα-regiovariation score analysis (results not shown).
FIG. 6
FIG. 6
Core structures within the PTP domain are highly conserved and surface loops between secondary structure elements are least conserved. Shown is a ribbon diagram indicating the positions of conserved motifs (M1 to M10) within the tertiary structure. The degree of conservation was determined from Cα-regiovariation score analysis of 37 aligned human PTP catalytic domains (see Fig. 5). Areas of conservation (blue, most conserved; red, least conserved) are illustrated using the PTP1B catalytic domain as the representative tertiary structure. Shown is the front view of PTP1B looking into the active site. The catalytically essential Cys215 residue is shown in yellow.
FIG. 7
FIG. 7
PTP domains from cytoplasmic PTPs and RPTP domains D1 and D2 show significant differences in their conservation of surface-exposed amino acids. Shown is surface conservation (blue, most conserved; red, least conserved) of PTP domains from nontransmembrane PTPs (A), RPTP domains D1 (B), and RPTP domains D2 (C). Shown is the front view looking into the active site. Cα-regiovariation score values for the cytoplasmic PTPs are illustrated using the X-ray crystal structure of PTP1B with the catalytically essential Cys215 (yel low) and epidermal growth factor receptor-derived peptide (green) bound within the active site (closed conformation). For ease of comparison, Cα-regiovariation score values among RPTP domains D1 and D2 sequences are illustrated using the X-ray crystal structure of RPTPα domain D1 (50). The EGFR peptide (green) is modeled in the active site of RPTPα for orientation using only a closed conformation of the X-ray crystal structures. Amino acids are labeled according to the residue position in human PTP1B with the equivalent residues in RPTPα given in brackets (A and B). The conserved four-residue structural linker located at the N terminus of domain D2 (encircled area 1 in panel C), and which constrains the relative orientation of tandem PTP domains in LAR, is compared to the corresponding nonconserved area for the RPTP domain D1 sequences (encircled area 1 in panel B). The amino acid residues defining this conserved linker are boxed and colored yellow in the alignment in Fig. 1.
FIG. 8
FIG. 8
Identification of novel conserved area on surface of PTP domain opposite active site. Shown are surface conservation (Cα-regiovariation score values) among nontransmembrane PTPs (A), RPTP domains D1 (B), and RPTP domains D2 (C). The tertiary structure is rotated 180° compared to structures in Fig. 7, showing the surface of the molecule opposite the active site. Encircled area II (B and C) corresponds to the interface for domains D1 and D2 as revealed in the X-ray crystal structure of LAR (56). Encircled area III is a novel putative interactive site, which appears to be conserved in all three subsets of PTP domain sequences. Amino acids are labeled according to the residue positions in PTP1B (A) and RPTPα (B and C).
FIG. 9
FIG. 9
Nonconserved amino acids in the proximity of the PTP active site are involved in the recognition of PTP substrates and nonpeptide PTP inhibitors. Shown is the visualization of four selectivity-determining regions on the molecular surface of PTP1B. Areas of conservation (blue, most conserved; red, least conserved) represent the Cα-regiovariation score values of 37 aligned human PTP catalytic domains (values from Fig. 5). The amino acids involved in defining these four selectivity-determining regions are indicated (boxed) in the alignment in Fig. 1.
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