A novel family of P-loop NTPases with an unusual phyletic distribution and transmembrane segments inserted within the NTPase domain
© Aravind et al.; licensee BioMed Central Ltd. 2004
Received: 19 January 2004
Accepted: 11 March 2004
Published: 16 April 2004
Recent sequence-structure studies on P-loop-fold NTPases have substantially advanced the existing understanding of their evolution and functional diversity. These studies provide a framework for characterization of novel lineages within this fold and prediction of their functional properties.
Using sequence profile searches and homology-based structure prediction, we have identified a previously uncharacterized family of P-loop NTPases, which includes the neuronal membrane protein and receptor tyrosine kinase substrate Kidins220/ARMS, which is conserved in animals, the F-plasmid PifA protein involved in phage T7 exclusion, and several uncharacterized bacterial proteins. We refer to these (predicted) NTPases as the KAP family, after Kidins220/ARMS and PifA. The KAP family NTPases are sporadically distributed across a wide phylogenetic range in bacteria but among the eukaryotes are represented only in animals. Many of the prokaryotic KAP NTPases are encoded in plasmids and tend to undergo disruption to form pseudogenes. A unique feature of all eukaryotic and certain bacterial KAP NTPases is the presence of two or four transmembrane helices inserted into the P-loop NTPase domain. These transmembrane helices anchor KAP NTPases in the membrane such that the P-loop domain is located on the intracellular side. We show that the KAP family belongs to the same major division of the P-loop NTPase fold with the AAA+, ABC, RecA-like, VirD4-like, PilT-like, and AP/NACHT-like NTPase classes. In addition to the KAP family, we identified another small family of predicted bacterial NTPases, with two transmembrane helices inserted into the P-loop domain. This family is not specifically related to the KAP NTPases, suggesting independent acquisition of the transmembrane helices.
We predict that KAP family NTPases function principally in the NTP-dependent dynamics of protein complexes, especially those associated with the intracellular surface of cell membranes. Animal KAP NTPases, including Kidins220/ARMS, are likely to function as NTP-dependent regulators of the assembly of membrane-associated signaling complexes involved in neurite growth and development. One possible function of the prokaryotic KAP NTPases might be in the exclusion of selfish replicons, such as viruses, from the host cells. Phylogenetic analysis and phyletic patterns suggest that the common ancestor of the animals acquired a KAP NTPase via lateral transfer from bacteria. However, an earlier transfer into eukaryotes followed by multiple losses in several eukaryotic lineages cannot be ruled out.
The P-loop NTPase domains constitute one of the largest apparently monophyletic groups of globular protein domains in the proteomes of most cellular organisms [1, 2]. These domains are implicated in nearly all biochemical and mechanical processes in the cell, including translation, transcription, replication and repair, intracellular trafficking, membrane transport, and activation of various metabolites [1, 3]. At the sequence level, most of the P-loop domains are characterized by two conserved motifs, termed the Walker A and B motifs . Structurally, P-loop domains adopt a globular fold with at least 5 α/β units (the P-loop NTPase fold), with the strands typically forming a core parallel sheet [5, 6]. The Walker A motif (typically, Gx4GK[T/S], where x is any residue) encompasses the first strand and helix, and is involved in binding the triphosphate moiety of the substrate NTP. The Walker B motif (typically, hhhhD, where h is a hydrophobic residue) encompasses the third universally conserved strand in the P-loop NTPase fold and coordinates a Mg2+ ion which directs an attack on the bond between the β and γ phosphates of the NTP [1, 3, 4].
Recognition of these distinctive sequence and structural features allows classification of uncharacterized P-loop NTPase families into one of the principal divisions and facilitates predictions of their potential catalytic capacity. Systematic analysis of the P-loop NTPases further demonstrated that most of the conserved families of the ASCE division ATPases could be confidently placed within one of the six large classes mentioned above . However, several families of ASCE NTPases remained outside this classification scheme. Here, we apply sequence and structural analysis to characterize one such previously unexplored family, which includes animal proteins participating in neural development and receptor tyrosine kinase signaling, and prokaryotic plasmid-encoded proteins that confer resistance to bacteriophages. We investigate the evolutionary implications of their unusual phyletic distribution and their unique structural feature, namely the insertion of multiple transmembrane helices into the P-loop NTPase fold. We also present predictions regarding their potential biochemical roles in eukaryotes and bacteria.
Results and discussion
Identification and classification of the KAP family of predicted ATPases
During our systematic analysis of the P-loop NTPase fold, we detected the mammalian neuronal membrane protein named kinase D-interacting substance of 220 kDa (Kidins220) or ankyrin repeat-rich membrane spanning protein (ARMS) [15, 16] in various searches initiated with position-specific scoring matrices (PSSMs) for different ASCE division ATPases, such as the AAA+ class. The alignments produced in these searches indicated that the ARMS protein contained the characteristic sequence signatures of the Walker A and B motifs. However, examination of these alignments also showed that ARMS contained one or more long inserts (>100 amino acid residues) within the potential P-loop NTPase domain.
To further investigate the structure and evolutionary connections of this protein, we performed PSI-BLAST searches (expectation value of 0.01 for inclusion of sequences into the PSSM, with the statistical correction for compositional bias) using as the query the sequence of the putative P-loop NTPase domain of ARMS (GenBank identifier gi: 14133247, residues 433-959). The first iteration of this search retrieved apparent orthologs of ARMS from other animals, such as Danio, Drosophila, Anopheles and Caenorhabditis, and a homolog from the cyanobacterium Anabaena. The subsequent iterations also detected, with significant E-values (e < 10-5) apparent divergent homologs from bacteria spanning a broad phyletic range (Figure 1). A possible pseudogene belonging to this family was also detected in the genomes of the archaea Methanococcus jannaschii and Methanosarcina (see below). The prokaryotic proteins detected in these searches included the PifA protein, which is encoded in the enterobacterial F plasmid and is required for exclusion of bacteriophage T7 [17, 18]. All these proteins contain the typical Walker A and B signatures, suggesting that they are functional P-loop NTPases. In contrast to the animal ARMS orthologs, most of the bacterial proteins, except for those from Anabaena species, Geobacter sulfurreducens and Microbulbifer degradans, lacked the large inserts within the P-loop NTPase domain. Reciprocal PSI-BLAST searches initiated with these bacterial proteins as queries first retrieved a consistent set of proteins that included the animal ARMS orthologs before the retrieval of other ASCE NTPases, such as the AP/NACHT-NTPases, AAA+ and ABC classes. These observations suggested that ARMS homologs define a novel group of P-loop NTPases that is distinct from all the previously described classes of P-loop domains. Hereinafter, we refer to them as the KAP family of (predicted) NTPases (after Kidins220/ARMS and PifA). In addition, the above searches retrieved a vertebrate paralog of the ARMS protein (for example, Rattus norvegicus protein LOC308414), in which Walker A and B motifs are disrupted (Figure 1), indicating that, unlike other ARMS homologs, it might lack NTPase activity.
To further explore the functional features and evolutionary relationships of the KAP family, we constructed a multiple alignment of the KAP proteins and compared its sequence conservation pattern and predicted secondary structure with those of other P-loop NTPases (Figure 1). The Walker B motif in the KAP family sequences typically has the form hhhhD[D/G]hD (where h is any hydrophobic residue). The second aspartate (D) immediately after the Walker B aspartate (first aspartate) is present in most of the bacterial KAP domains but is replaced by a glycine or an alanine in the animal sequences (Figure 1). An acidic residue in this position is an ancestral feature of the ASCE division of ATPases, and the presence of an aspartate is specifically characteristic of the AP/NACHT-NTPases as opposed to the glutamate, which is most common in the SFI/II helicase and AAA+ ATPases [7, 13, 14, 19, 20]. Furthermore, the third aspartate located three positions downstream of the Walker B aspartate is a shared feature of the KAP and NACHT families . In the KAP family proteins, one of these aspartates might function as the proton-abstracting negative charge in NTP hydrolysis. The KAP family proteins contain another conserved polar residue (typically, D) at the end of strand 4 (Figure 1). This feature is also characteristic of the ASCE NTPases and corresponds to the sensor I motif of the AAA+ domains and its counterparts in other proteins of the ASCE division [7, 11, 14]. These conserved features, together with the consistent detection of various ASCE NTPases in database searches with the profiles of KAP family PSSM, strongly suggest that this family belongs to the ASCE division.
Most of the NTPases of the KAP family have a variable α-helical insert amino-terminal to the Walker B motif. Remarkably, all animal KAP NTPases and three bacterial ones, those from Anabaena, G. sulfurreducens and Microbulbifer, contain two membrane-spanning helices inserted in this region (Figures 1, 2). The animal proteins additionally contain two more transmembrane helices inserted in the region between helix 1 (associated with the Walker A motif) and strand 2 of the core NTPase domain. Insertion of membrane-spanning helices into globular domains is extremely rare in proteins , and, to our knowledge, the KAP family is the first such instance among P-loop NTPase domains. In the NTPase domains that do not form ring structures, most residues involved in NTP-binding and hydrolysis are located at the carboxy termini of the strands forming the core parallel β-sheet (Figures 1, 2). This causes a polarity in the structure of the NTPase domain with respect to the location of catalytic surface, thus allowing it to accrete inserts in regions that are spatially disjointed from this catalytic surface. This might explain the ability of the KAP NTPase domain to retain its structural and functional integrity despite the insertion of transmembrane helices. Superposition of the multiple alignment of the KAP family onto known structures of the P-loop NTPase domains suggests that the membrane-spanning inserts project outward from the conserved intracellular globular core, probably from the surface opposite to the NTP-binding surface (Figure 2).
Prediction of functional features of the KAP NTPases
In mammals, Kidins220/ARMS localizes to the tips of neurites and is abundantly expressed in the neural tissues in regions that are enriched in receptors for ephrins and ligands of the neurotrophin family. Furthermore, Kidins220/ARMS physically interacts with TrkA and p75 neurotrophin receptors and is phosphorylated upon activation of the neutrophin and ephrin receptors [15, 16]. Kidins220/ARMS also appears to be a physiological substrate for protein kinase D, suggesting that it might be a key target for multiple neuronal signaling cascades [15, 16]. Kidins220/ARMS and all its animal orthologs contain 10 or more amino-terminal ankyrin repeats , while the Anabaena homolog with transmembrane segments contains approximately 40 TPR repeats amino-terminal to the P-loop NTPase domain . Similarly, the membrane-associated KAP proteins from Microbulbifer and G. sulfurreducens contain a large amino-terminal segment with predicted coiled-coil structure. Phosphorylation of Kidins220/ARMS by various kinases suggests that this protein might function as a signaling nexus associated with the cell membrane. The α-superhelical structure domains present in animal (and some bacterial) KAP NTPases, such as ankyrin and TPR repeats, could provide extended surfaces to mediate interactions with various protein complexes. The likely function for the KAP NTPase domain is the regulation of assembly/disassembly of these complexes in an NTP-dependent manner. In particular, Kidins220/ARMS and the orthologous KAP NTPases in other animals might regulate the assembly of neurite-membrane-associated signaling complexes that are positioned downstream of different receptor tyrosine kinases in the respective signaling pathways. Consistent with this proposal, the high-throughput screens for protein-protein interactions in Drosophila recovered the PDZ-domain protein Dlg, which binds the carboxy-terminal tails of neural membrane proteins, as an interacting partner for the Kidins220/ARMS ortholog . The vertebrate paralogs of Kidins220/ARMS with apparently inactive NTPase domains lack the ankyrin repeats and might function as dominant-negative regulators of active KAP NTPases.
The bacterial KAP proteins without the transmembrane regions contain a variable helical insert (Figure 1), which could function as a site for interactions with other proteins. The prokaryotic KAP family members have not been characterized biochemically, but potential leads to their functions are suggested by the available data on the PifA protein, which is encoded in enterobacterial F plasmids and is required for exclusion of bacteriophage T7 from plasmid-containing cells [17, 18]. The exclusion process involves interactions between PifA and the products of T7 genes 1.2 and 10, which code for the major phage capsid proteins, and is accompanied by an increase in membrane permeability [17, 25]. These observations imply that PifA might reorganize certain membrane-associated complexes in an ATP-dependent manner and thereby disrupt the T7 life cycle. While it is not clear whether the principal function of PifA is in bacteriophage exclusion, some other lines of circumstantial evidence support this possibility.
In prokaryotic genomes, genes coding for functionally interacting proteins often co-occur in conserved operons or form gene fusions to give rise to a single gene. Consequently, evolutionarily conserved juxtaposition of functionally uncharacterized genes with genes whose functions are known has the potential to throw light on the functions of the former [27–29]. In the case of KAP NTPases, a conserved gene neighborhood was detected in E. coli (strain cft073), Deinococcus radiodurans plasmid CP1, and Agrobacterium tumefaciens plasmid AT, in which the gene for the KAP NTPase is located next to genes encoding a TIM barrel DNase of the TatD family  and an ATP pyrophosphohydrolase of the PP-loop fold . Although the exact functional implications of this linkage are unclear, it seems likely that these enzymes cooperate with the KAP NTPases in the inhibition of phage reproduction; the DNase, in particular, is a candidate for a role in degradation of phage DNA.
Evolution of the KAP NTPase family
Phylogenetic trees of the conserved NTPase domain of the KAP family were constructed using the maximum likelihood, neighbor-joining, and minimum evolution methods (see Materials and methods for details). The trees constructed with each of these methods had similar topologies and suggested existence of several subfamilies within the KAP family. One of these, the ARMS subfamily, includes all animal KAP proteins and three bacterial members, those from M. degradans, G. sulfurreducens and Anabaena (Figure 3). In this case, phylogenetic analysis strongly supported monophyly of this group, which was independently suggested by their shared derived character, the insertion of transmembrane helices into the P-loop domain. A second subfamily consists of proteins from phylogenetically diverse bacteria, such as E. coli (strain cft073), D. radiodurans plasmid CP1, A. tumefaciens plasmid AT, Ralstonia and Magnetococcus, and is also supported by an apparent shared derived character, a carboxy-terminal globular domain that is unique to this subfamily. This bacterial subfamily groups with the ARMS subfamily, to the exclusion of homologs from all other prokaryotes (Figure 3). The third major subfamily includes the F-plasmid-borne PifA and its homologs from plasmids and chromosomes of Klebsiella, Pseudomonas, Corynebacterium, Nostoc, Thermotoga, Clostridium and Leuconostoc. The validity of this family is supported by the presence of a unique carboxy-terminal domain that shows no obvious relationships with any previously conserved globular domains.
Thus, on more than one occasion, the phylogenetic tree of the KAP family brings together phylogenetically distant bacteria (for example, Deinococcus, Agrobacterium and E. coli) in well-supported clades, strongly suggesting a major role of plasmid-mediated horizontal transfer in the evolution of this family (Figure 3). The most striking feature of the tree is the nesting of the animal ARMS homologs within a clade containing bacterial members. Among the currently available members of the KAP family, the greatest diversity is seen in bacteria, and almost all subfamilies contain multiple plasmid-borne members. It seems likely that the original KAP NTPase evolved on a bacterial plasmid and had a role in the modification of the bacterial membrane that results in exclusion of bacteriophages from the plasmid-carrying bacteria. Subsequently, the KAP NTPase in one of the bacterial lineages acquired the pair of transmembrane helices inserted into the P-loop domain, which made it an integral membrane protein. The apparent preponderance of horizontal gene transfer in the evolution of the KAP family and the phylogenetic affinities of the animal KAP NTPases suggest that the gene for a membrane-spanning KAP NTPase was laterally transferred to eukaryotes before the divergence of the major animal lineages, probably from a bacterial plasmid or chromosome. As no eukaryotes other than animals are currently known to have a KAP NTPase, it seems likely that this gene transfer occurred relatively late in evolution - that is, after the separation of the lineage leading to the animals from other crown-group eukaryotes. However, given the sparse sampling of large eukaryotic genomes from different crown-group lineages, the possibility remains that the transfer occurred earlier, but KAP genes have been lost in the currently sampled taxa.
Evidence of independent insertion of transmembrane helices in other P-loop NTPase domains
We describe here a previously unnoticed family of P-loop NTPases that displays unusual structural features and phyletic patterns. The P-loop NTPase domain of this family, designated the KAP family, belongs to the ASCE division of P-loop NTPases and might be distantly related to the AAA+ and AP/NACHT NTPases [10, 11, 13]. All eukaryotic and several bacterial members of the KAP family contain two or four transmembrane segments inserted into the P-loop NTPase domain and, accordingly, are predicted to be integral membrane proteins, with the P-loop domain attached to the intracellular side of the membrane. In addition, we identified another small family of predicted bacterial NTPases, which do not seem to be specifically related to the KAP family, but also contain two transmembrane helices inserted into the P-loop domain. Insertion of transmembrane helices into globular domains is generally rare and, to our knowledge, has not been described in P-loop NTPases so far. It is well known, however, that the P-loop domain tolerates extremely long inserts of hydrophilic domains, such as the coiled-coil domains in the SMC family ATPases involved in chromatin dynamics and repair [32, 33]. Furthermore, many P-loop NTPases are involved in membrane transport and secretion. In particular, these are the principal functions of the ABC-class ATPases, and some of these, such as the CFTR protein in animals, contain multiple transmembrane helices, which, however, are located outside the P-loop domain . The discovery of two families of predicted P-loop NTPases with transmembrane helices inserted into the P-loop domain itself unifies these two structural themes and further expands our notion of the enormous structural and functional plasticity of this widespread domain.
Among eukaryotes, the KAP family is so far represented only in animals and is typified by the neuronal membrane protein Kidins220/ARMS and its paralog, which seems to have a catalytically inactive NTPase domain. In prokaryotes, KAP NTPases are often encoded by plasmids and might function in exclusion of bacteriophages from the plasmid-bearing bacterial cells. We predict that both eukaryotic and bacterial KAP NTPases regulate NTP-dependent assembly or disassembly of membrane-associated protein complexes. Phyletic pattern and phylogenetic analysis suggest that lateral transfer from bacteria to the animal lineage (or an earlier ancestral form) before the diversification of the latter gave rise to the ancestor of the eukaryotic KAP NTPases. However, given the evidence of rampant gene loss in diverse eukaryotes [35, 36], it is conceivable that the KAP NTPases were acquired early in eukaryotic evolution and subsequently lost in several non-animal lineages. Regardless of the exact origin scenario, these NTPases provide a remarkable example of recruitment of a protein originally acquired from bacteria for animal-specific functions, such as receptor tyrosine kinase-mediated signaling in neural growth and development.
Materials and methods
The non-redundant (NR) database of protein sequences (National Center for Biotechnology Information, NIH, Bethesda) was searched using BLASTP . Iterative database searches were conducted using PSI-BLAST with either a single sequence or an alignment used as the query, with the PSSM inclusion expectation (E) value threshold of 0.01 (unless specified otherwise); the searches were iterated until convergence . For all searches with compositionally biased proteins, the statistical correction for this bias was used [38, 39]. Multiple alignments were constructed using the T_Coffee or PCMA programs, followed by manual correction based on the PSI-BLAST results [40, 41]. All large-scale sequence analysis procedures were carried out using the SEALS package . Transmembrane regions were predicted in individual proteins using the TMPRED , TMHMM2.0  and TOPRED1.0  programs with default parameters. For TOPRED1.0, the organism parameter was set to 'prokaryote' or 'eukaryote' depending on the source of the protein.
Protein-structure manipulations were performed using the Swiss-PDB viewer program  and the ribbon diagrams were constructed using the MOLSCRIPT program . Protein secondary structure was predicted using a multiple alignment as the input for the PHD program . Similarity-based clustering of proteins was carried out using the BLASTCLUST program .
Phylogenetic analysis was carried out using the maximum-likelihood, neighbor-joining, and minimum evolution (least squares) methods. Maximum-likelihood distance matrices were constructed with the TreePuzzle 5 program using 1,000 replicates generated from the input alignment and used as the input for construction of neighbor-joining trees with the Weighbor program [50, 51]. Weighbor uses a weighted neighbor-joining tree construction procedure that has been shown to correct effectively for long-branch effects . The minimal evolution trees were constructed using the FITCH program of the Phylip package,  followed by local rearrangement using the Protml program of the Molphy package  to produce the maximum likelihood (ML) tree. The statistical significance of the internal nodes of the ML tree was assessed using the relative estimate of logarithmic likelihood bootstrap (Protml RELL-BP), with 10,000 replicates . A full ML tree was constructed using the Proml program of the Phylip package . This tree was used as the input tree to generate further full ML trees using the PhyML program with 100 bootstrap replicates generated from the input alignment . The consensus of these trees was derived using the Consense program of the Phylip package to obtain the bootstrapped ML tree . A gamma distribution with one invariant and eight variable sites with different rates was used in the ML analysis. Gene neighborhoods were determined by searching the NCBI PTT tables with a custom-written script. These tables can be accessed from the genomes division of the Entrez retrieval system.
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