Different Protein Tyrosine Phosphatase Superfamilies Resulting from Different Gene Reading Frames

Jing-Fei Huang

Yunnan Key Laboratory of Molecular Biology of Domestic Animals, and the Key Laboratory of Cellular and Molecular Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China


    Abstract
 TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 Literature Cited
 
Protein tyrosine phosphatases (PTPs) are comprised of two superfamilies, the phosphatase I superfamily containing a single low-molecular-weight PTP (lmwPTP) family and the phosphatase II superfamily including both the higher-molecular-weight PTP (hmwPTP) and the dual-specificity phosphatase (DSP) families. The phosphatase I and II superfamilies are often considered to be the result of convergent evolution. The PTP sequence and structure analyses indicate that lmwPTPs, hmwPTPs, and DSPs share similar structures, functions, and a common signature motif, although they have low sequence identities and a different order of active sites in sequence or a circular permutation. The results of this work suggest that lmwPTPs and hmwPTPs/DSPs are remotely related in evolution. The earliest ancestral gene of PTPs could be from a short fragment containing about 90~120 nucleotides or 30~40 residues; however, a probable full PTP ancestral gene contained one transcript unit with two lmwPTP genes. All three PTP families may have resulted from a common ancestral gene by a series of duplications, fusions, and circular permutations. The circular permutation in PTPs is caused by a reading frame difference, which is similar to that in DNA methyltransferases. Nevertheless, the evolutionary mechanism of circular permutation in PTP genes seems to be more complicated than that in DNA methyltransferase genes. Both mechanisms in PTPs and DNA methyltransferases can be used to explain how some protein families and superfamilies came to be formed by circular permutations during molecular evolution.

Key Words: circular permutation • different gene reading frames • divergent and convergent evolution • gene duplication and fusion • molecular evolution • protein tyrosine phosphatase


    Introduction
 TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 Literature Cited
 
Protein tyrosine phosphorylation and dephosphorylation are central reactions for control of cellular division, differentiation, and development (Murray 1992). Protein tyrosine phosphatases (PTPs) play an important role during dephosphorylation, a process that can remove phosphoryl groups from phosphotyrosine-containing proteins. Protein tyrosine phosphatases include low-molecular-weight PTPs (lmwPTPs), higher-molecular-weight PTPs (hmwPTPs), and dual-specificity phosphatases (DSPs). These are often considered to belong to two superfamilies, the phosphatase I superfamily containing a single lmwPTP family and the phosphatase II superfamily including both the hmwPTP and the DSP families (Stone and Dixon 1994; Barford, Jia, and Tonks 1995; Murzin et al. 1995). Convergent evolution between phosphatase I and II has been suggested (Stone and Dixon 1994; Barford, Jia, and Tonks 1995) because of low sequence identities, similar topologies, and a different order of the active site residues in sequence, or a circular permutation.

Protein convergent evolution may be caused by physical and chemical restraints of a broadly analogous function requirement where there is a topological equivalency but no convincing sequence or functional similarity. When this is the case, convergent evolution appears quite likely (Bajaj and Blundell 1984; Murzin 1998). The significant sequence similarity usually implies that homology; however, proteins with the same fold and similar or related functions but very different sequences may also be the result of divergent evolution from a common ancestor (Rossmann and Argos 1977; Bajaj and Blundell 1984). Circular permutations are a frequent event in molecular evolution, and they have been observed in many protein families and superfamilies (Lindqvist and Schneider 1997). Some of them have been confirmed to be the results of divergent evolution (Malone, Blumenthal, and Cheng 1995; Ponting and Russell 1995; Lupas 1996). Furthermore, the evolutionary mechanism of circular permutation in DNA methyltransferase genes has also been illustrated (Jeltsch 1999).

Thus, a divergent evolution between lmwPTPs, hmwPTPs/DSPs is still probable. To argue about divergent or convergent evolution between PTPs, the structures and sequences of these three PTP families are compared and analyzed further in this work. The results suggest that the lmwPTPs and hmwPTPs/DSPs should belong to the distant homologous proteins, and that they may have resulted from circular permutations or different reading frames of genes; the evolutionary mechanism of circular permutation in PTP genes seems to be more complicated than that in DNA methyltransferase genes, although the mechanisms of circular permutations in the two enzymes are similar.


    Materials and Methods
 TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 Literature Cited
 
The structural data of PTPs are from the Protein Data Bank (PDB) (Berman et al. 2000), and three-dimensional structures of one hmwPTP (PDB code: 2hnq), one DSP (1vhr), and one lmwPTP (1phr) are superposed by the programs of MNYFIT (Sutcliffe et al. 1987) and SAP (Taylor 2000). The structure-based alignment of PTP domain sequences has been performed with COMPARER (ali and Blundell 1990) and with SAP. To obtain an alignment, we omitted a segment before the 35th residue in the 1phr sequence and linked that segment to its C-terminal; in addition, some large insertion regions in sequence have been deleted. The results of PTP structure superpositions and structure-based alignments obtained from different programs are checked by graphics.

The sequences of 1phr, 2hnq, and 1vhr from PDB are taken as the seeds with which to search the NR (all nonredundant GenBank CDS translations + PDB + SwissProt + PIR + PRF) database and the MGBD (Microbial Genomes Blast Databases) at the (US) National Center for Biotechnology Information (NCBI) by PSI-Blast (Altschul et al. 1997). E values <=0.005 are used in the database searches. The sequences hit by seeds are analyzed and aligned by the ClustalW program (Thompson, Higgins, and Gibson 1994).

The sequence of 1phr is divided into four fragments, I, II, III, and IV, based on its structure, in which each fragment includes a ß-{alpha} structural element. All four fragments are aligned by ClustalW, and they are linked in four different orders; i.e., fragments I-II-III-IV, II-III-IV-I, III-IV-I-II, and IV-I-II-III. These fragments with the different orders are aligned with the different PTP sequences belonging to hmwPTPs, DSPs, or lmwPTPs.


    Results
 TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 Literature Cited
 
The structural superpositions of 1phr, 2hnq, and 1vhr show that the core structures of all PTPs are remarkably similar (fig. 1A), and that the side chains of active-site pockets can also be superposed (fig. 1B). The root mean square differences between superposed structures of the phosphatase I (1phr) and the phosphatase II are 1.51 with 2hnq and 1.44 with 1vhr, and the region from Cys12 to Arg18, corresponding to 1phr or P-loop, has been suggested as the active region of PTP (Kolmodin and qvist 2001). The structure-based sequence alignment of PTPs shows that the sequence identities between 1phr and 2hnq are very low (sequence identities = 7.19%), but the identities between 1phr and 1vhr are same as those between 2hnq and 1vhr, 11.51%; and 1phr, 2hnq, and 1vhr share one structurally equivalent signature motif, Cys-X5-Arg, and a proton donor residue, Asp (fig. 1C). The signature motif is located at the N-terminus in 1phr, but it is at the C-termini in the 2hnq and/or 1vhr, where residues Cys and Arg have been defined as the essential residues for catalytic activity (Streuli et al. 1990; Guan and Dixon 1991; Pot et al. 1991; Cho et al. 1992).



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FIG. 1. The comparisons of structures and sequences between 1phr, 2hnq, and 1vhr. A, The core structure superposition of 1phr, 2hnq, and 1vhr. Shaded cylindrical shapes: {alpha}-helices; thick arrow shapes: ß-strands; N: N-terminus; C: C-terminus; oval outline: P-loop or active region. B, Superposition of main chains (thick stick) and side chains (thin stick) in PTP active regions; Cys and Arg: active residues; PO-4: the phosphate group of PTP substrate. C, The structure-based sequence alignment between 1phr, 2hnq, and 1vhr; box: the common conserved active regions between lmwPTPs, hmwPTPs, and DSPs; vertical arrow: the active site and proton donor residues; solid triangle: N-terminal residue Val 4 in 1phr. The sequence identities between 1phr, 2hnq, and 1vhr are listed under the alignment

 
The results of the NR and MGBD database searches show that the distributions of three different families of PTPs in various genomes are significantly different. Specifically, lmwPTPs cannot be hit in viruses, but both hmwPTPs and DSPs can be hit in eubacteria, archaea, eukaryotae, and viruses. The lmwPTPs in bacteria, including eubacteria and archaea, are over 64%, but hmwPTPs and DSPs in bacteria are below 7% (fig. 2). In general, there are more PTP gene copies in eukaryotae genomes than in bacteria or viruses. Many eukaryotae contain more than one PTP gene copy, but almost all eubacteria contain only one PTP copy (fig. 2; also see online Supplementary Material). This suggests that PTP genes have been duplicated in eukaryotae and some bacteria, implying that the dephosphorylation in bacteria is dependent mainly on lmwPTPs. In contrast, this function in eukaryotes and viruses is performed mainly by hmwPTPs and DSPs; in addition, because most of the PTPs in bacteria are lmwPTPs, it appears that lmwPTPs could occur in living organisms earlier than DSPs/ hmwPTPs.



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FIG. 2. Taxonomic distributions of sequences matched against protein tyrosine phosphatases in NR database. 1. lmwPTPs; 2. hmwPTPs; and 3. DSPs

 
In some bacteria genomes, the sequences matched against 1phr, 2hnq, and 1vhr can be hit in the same genome; for example, all of them can be observed in the archaea Pyrococcus furiosus; the sequences matched against 1phr and 1ypt (one of the hmwPTPs) can be hit in Salmonella typhimurium LT2; and those matched against 1phr and 1vhr can be found in Desulovibrio vulgaris. The sequences matched against 2hnq/1ypt and 1vhr have been observed in the same gene, so clearly hmwPTPs and DSPs come from a common ancestral gene. Those matched against 1phr and 2hnq/1ypt/1vhr, however, cannot be observed in the same gene, even though they are in the same genome.

Some traces of PTP gene duplications and fusions can be observed in several genomes. The results of database searches show that Q9VFR9 (SWISS-PROT code) in the Drosophila melanogaster genome contains three continuous copies belonging to one transcription unit, and this transcription unit has been defined as lmwPTP in FlyBase (FlyBase code: primo-1 CG9599). These three copies are obviously homologous, and they are also similar to the Ptp61F gene product (Entrez code: AAF47487) belonging to hmwPTPs in sequence (fig. 3A). PTPA_Human (SWISS-PROT code: P18433) is comprised of 802 residues, in which residue 241~500 and residue 501~802 correspond to domain 1 (PTP 1) and domain 2 (PTP 2), respectively (fig. 3B); the two regions from Cys442 to Arg448 in PTP 1 and from Cys732 to Arg738 in PTP2 correspond to the hmwPTP active motif, and PTP 1 and PTP 2 are significantly homologous in sequence (sequence identities = 32.66%); the sequence alignments between residue 431~598 of PTPA_Human and 1phr show that they share a common active motif, although their sequence identities are just 10.71% (fig. 3B). Open reading frames (ORFs) -9 and -10 in the Orgyia pseudotsugata single capsid nuclear polyhedrosis virus genome encode two DSP domains; however, in ORF-10, two regions A, located at the N-terminus and at the C-terminus, correspond to the active regions of lmwPTPs and DSPs/hmwPTPs, respectively. The sequence identities between residues 8 and 216 of ORF-10 and residue 1~157 of 1phr are 20.09% (fig. 3C), but the identities between residue 1~220 of ORF-10 and residue 10~286 of 2hnq are just 18.79% (fig. 3D).



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FIG. 3. Some traces of PTP gene duplications and fusions. A, The transcription unit of Q9VFR9 and its sequence alignment with ptp61F. B, Gene structure and arrangement of human PTPA, and sequence similarities of PTPA (domain 1 and domain 2) with 1phr; S: the signal region; Ex: the extracellular region; TM: the transmembrane region; residue 165–802: the intracellular region; residue 241–500: protein-tyrosine-phosphatase 1 (domain 1); residue 501–802: protein-tyrosine-phosphatase 2 (domain 2). Two regions A in the ORF-10 sequence can correspond to the active site regions of 1phr (C) and 2hnq (D), respectively. Box A: the active regions of lmwPTPs or hmwPTPs/DSPs

 

    Discussion
 TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 Literature Cited
 
Previous studies have suggested that PTPs belong to two superfamilies, phosphatase I and phosphatase II, because the sequence identities between phosphatase I and II are very low, and their active sites are very different in sequence. That is, the active sites in phosphatase I are located at N-termini, but they are at C-termini in phosphatase II. However, remarkably, all PTPs with a different order of active sites can share a similar core structure (fig. 1A), conserved side-chains in critical functional residues (fig. 1B), the same function (Guan and Dixon 1991; Barford, Jia, and Tonks 1995; Murphy, Tibbitts, and Kantrowitz 1995; Kolmodin and qvist 2001), a catalytic mechanism (Streuli et al. 1990; Guan and Dixon 1991; Pot et al. 1991; Cho et al. 1992; Murphy, Tibbitts, and Kantrowitz 1995), and a common sequence motif (Huang and Liu 2002; fig. 1C). Some previous studies have suggested that the proteins with all these features in PTPs may be remotely related in evolution (Bajaj and Blundell 1984; Malone, Blumenthal and Cheng 1995; Murzin 1998).

Sequence analyses show that not only are the sequence identities between lmwPTPs and hmwPTPs/DSPs very low, but also that those between hmwPTPs and DSPs are low. The structure-based sequence alignment indicates that the sequence identities between 1phr and 1vhr are same as those between 2hnq and 1vhr (fig. 1C). Even the sequence identities between several lmwPTPs and hmwPTPs are higher than those between some hmwPTPs and DSPs; for example, the maximum identities between one hmwPTP (1ypt) and 1phr are 22.79%, but the maximum identities between another hmwPTP (1yfo) and 1vhr are just 20.45% (see online Supplementary Material). In addition, lmwPTPs and hmwPTPs/DSPs share a common signature motif equivalent in structure and function, and more than 98% of the sequences hits from databases by this motif are lmwPTPs and hmwPTPs/DSPs (Huang and Liu 2002). So, the sequence differences between the lmwPTPs, hmwPTPs, and DSPs are not remarkable. Generally, the active sites of PTPs are located at N-termini of lmwPTPs and at C-termini of hmwPTPs/DSPs, but they are also observed at or close to N-termini in several hmwPTPs/DSPs—for example, the protein-tyrosine phosphatase domain (Entrez code: AAB52357; gi_1938556) in Caenorhabditis elegans, the dual specificity phosphatase 5 (Entrez code: XP_067629.1; gi_17445380), and the human nonreceptor tyrosine phosphatase 1 (Entrez code: AAA60158; gi_190279) (see online Supplementary Material). Thus, it is not enough to define the evolutionary relationship between all PTP families based only on the identities and positions of PTP active sites in sequence.

The 1phr structure defined by X-ray is comprised of four sequence fragments, and each fragment contains a ß-{alpha} structural element. In this work, the four fragments are termed fragments I, II, III, and IV, and the active-site regions of lmwPTPs are in fragment I (fig. 4A; also see online Supplementary Material). The sequence analyses show that the maximum identities between two lmwPTP sequences, 1jf8 (arsenate reductase ArsC) and 1phr, are 23.53%, but the maximum sequence identities between fragments I and II in 1phr have been 21.74%, and some residues in the active-site region of fragment I are also obviously conserved in fragment II (see online Supplementary Material). These findings suggest that fragments I and II may be the result of gene duplication. In fact, the sequence homologies can be observed in all four fragments. Thus the four fragments in 1phr may be the result of gene internal duplications. Similar internal duplication events have also been observed in many proteins (Malone, Blumenthal, and Cheng 1995; Heringa and Taylor 1997).



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FIG. 4. PTP gene structure and evolution. A, The different arrangements of fragments I, II III, and IV in PTPs where I, II, III, and IV are the four fragments with ß-{alpha} structure element; and a, b, c, and d show the different orders of active sites in PTPs. B, Evolutionary scheme and circular permutations of PTP genes. The earliest ancestral gene of PTPs could be from a short fragment containing about 90~120 nucleotides or 30~40 residues; for example, the fragment I in lmwPTPs, by the duplications and fusions of this fragment. A probable full PTP ancestral gene that had contained one transcript unit with two lmwPTP genes can be formed by another gene duplication and fusion event. (1), (2), (3), (4), and circled 1, 2, 3, and 4 show four different reading frames in the PTP ancestral gene; and the vertical arrows and shaded triangles indicate the start and stop points of different gene reading frames respectively; right-pointing shaded arrow: ß–strand; cylindrical shape: {alpha}–helix; thin open rectangles: coil; thin solid rectangles: the active site region

 
To do further analysis, all four fragments of 1phr are linked in four different orders; i.e., fragments I-II-III-IV, II-III-IV-I, III-IV-I-II, and IV-I-II-III, and these fragments are aligned with three different PTP sequences belonging to hmwPTPs, DSPs, and lmwPTPs. The results show that the circular permutations in PTPs can be obtained by the different arrangements of fragments I, II, III, and IV (see online Supplementary Material), which suggests that the circular permutations in PTPs may result from reading genes differently (fig. 4B). Thus, the earliest ancestral gene of PTPs could be from a short fragment containing about 90~120 nucleotides or 30~40 residues—for example, fragment I in lmwPTPs—because the present lmwPTP gene can be formed by the duplications and fusions of this fragment. However, a probable full PTP ancestral gene that had contained one transcript unit with two lmwPTP genes can be formed by another gene duplication and fusion event (fig. 4B). In fact, a transcript unit with more than two lmwPTP genes—for example, Q9VFR9—has been observed in the genome of Drosophila melanogaster. The various types of hmwPTPs/DSPs include active sites located at N-, close to N-, close to C-, and at C-termini, except lmwPTPs, and they can be obtained by reading this transcript unit in different reading frames (fig. 4B). Thus, the three different PTP families may have resulted from a common ancestral gene by the duplications, fusions, and circular permutations. The circular permutation in PTPs is caused by reading genes differently, which is similar to the circular permutation in DNA methyltransferases described by Jeltsch (1999); nevertheless, the evolutionary mechanism of circular permutations in PTP genes seems to be more complicated than that in DNA methyltransferase genes. The two mechanisms in PTPs and in DNA methyltransferases can be used to explain how some protein families and superfamilies can be formed by circular permutations during molecular evolution.


    Acknowledgements
 TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 Literature Cited
 
The author thanks Tom Blundell and the anonymous referee for their very helpful comments, the Natural Science Foundation of China (Grant 30170507; 30024004) and the Natural Science Foundation of Yunnan Province (Grant 1999C0084M) for financial support.


    Footnotes
 
E-mail: hjf58117{at}public.km.yn.cn. Back

William Taylor, Associate Editor Back


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 Materials and Methods
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Accepted for publication January 21, 2003.





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