Molecular evolution of type VI intermediate filament proteins
© Guérette et al; licensee BioMed Central Ltd. 2007
Received: 28 May 2007
Accepted: 13 September 2007
Published: 13 September 2007
Tanabin, transitin and nestin are type VI intermediate filament (IF) proteins that are developmentally regulated in frogs, birds and mammals, respectively. Tanabin is expressed in the growth cones of embryonic vertebrate neurons, whereas transitin and nestin are found in myogenic and neurogenic cells. Another type VI IF protein, synemin, is expressed in undifferentiated and mature muscle cells of birds and mammals. In addition to an IF-typical α-helical core domain, type VI IF proteins are characterized by a long C-terminal tail often containing distinct repeated motifs. The molecular evolution of type VI IF proteins remains poorly studied.
To examine the evolutionary history of type VI IF proteins, sequence comparisons, BLAST searches, synteny studies and phylogenic analyses were performed. This study provides new evidence that tanabin, transitin and nestin are indeed orthologous type VI IF proteins. It demonstrates that tanabin, transitin and nestin genes share intron positions and sequence identities, have a similar chromosomal context and display closely related positions in phylogenic analyses. Despite this homology, fast evolution rates of their C-terminal extremity have caused the appearance of repeated motifs with distinct biological activities. In particular, our in silico and in vitro analyses of their tail domain have shown that (avian) transitin, but not (mammalian) nestin, contains a repeat domain displaying nucleotide hydrolysis activity.
These analyses of the evolutionary history of the IF proteins fit with a model in which type VI IFs form a branch distinct from NF proteins and are composed of two major proteins: synemin and nestin orthologs. Rapid evolution of the C-terminal extremity of nestin orthologs could be responsible for their divergent functions.
The intermediate filament (IF) family is composed of more than 70 genes that are expressed in a tissue- and developmental stage- specific manner in metazoan cells [1–3]. All IF proteins exhibit a tripartite structure comprising a central α-helical core domain flanked by globular head and tail regions . Members of the IF family are grouped together in a class of nuclear proteins (lamins: type V) along with four or five classes of cytoplasmic proteins (types I-IV, VI) depending on the criteria used for their classification [3–6]. Keratins represent the first two classes (types I and II) of IF proteins and they are obligatory heteropolymers. Keratin genes are the most abundant IF family members. In humans, they are clustered on chromosomes 17q21 (type I) and 12q13 (type II) . Vimentin, desmin, peripherin and GFAP form type III IF proteins that can assemble in filaments on their own, or in combination with type IV and type VI IF proteins. Neuronal IF proteins comprise NF-L (light), NF-M (medium), NF-H (heavy) neurofilament protein subunits that along with α-internexin are classified as type IV IF proteins.
Upon its identification in 1990, nestin was designated as the prototype of a new IF protein group (type VI) because it did not fall clearly into any of the previously described types . Some debate arose on this classification since nestin gene structure is closely related to the neurofilament branch in having two of its three intron positions in common with NF genes . Accordingly, it had been proposed to re-classify nestin as a type IV IF protein . However, the low level of sequence similarity of the α-helical region of nestin and NF proteins as well as the presence of a third intron in the nestin gene constitute strong arguments in favor of its classification as a distinct type [6, 8, 10]. Furthermore, the discovery of tanabin in Xenopus laevis a few years later led to the proposal that this tanabin protein could be the prototype of a different IF type (type VII) because of the lack of significant sequence similarities with other IF proteins . Shortly after nestin and tanabin were sequenced, the gene structures of synemin [12, 13] and transitin  were also described. According to their sequence similarities, tanabin was then grouped with transitin, paranemin (a splice variant of transitin), synemin and nestin as type VI IF proteins. All these proteins are distinguished by a long C-terminal extremity and by the fact that they cannot self-form into filaments. Rather, they need other IF proteins to build filamentous structures [10, 15].
Tanabin is specific to amphibians, transitin to birds and nestin to mammals. Tanabin is expressed during neurulation of X. laevis and its function is not well understood . Transitin and nestin are transiently expressed in myogenic and neurogenic cells of birds and mammals, respectively [6, 16–20]. Chicken transitin is co-expressed with vimentin in proliferating myoblasts and is associated for a short period of time with desmin at the Z line during muscle differentiation . Transitin expression persists in the smooth muscle cells of elastic arteries and in Purkinje fibers where it is expressed in association with vimentin . Its expression is also induced in activated Müller glial cells of chicken retinas following acute retinal damage . Paranemin, a splice variant of transitin , is important for the formation of an extended IF network when co-transfected with desmin in SW13 cells . Recently, transitin has been shown to play an important role in determining the intracellular localization of Numb in mitotic neuroepithelial cells . In mammals, nestin expression is induced in certain tumors as well as in regenerating skeletal muscles [25, 26]. In addition, nestin is implicated in vimentin intermediate filament disassembly during mitosis  and is a survival determinant through cdk5 regulation in oxidant-induced cell death . All these observations suggest that both transitin and nestin have important and distinct functions in various cell types during embryonic development and in tissue regeneration in adults.
Despite a low level of sequence identity, the large tail domains of nestin and transitin display some similarities including the presence of highly charged glutamate-rich stretches and of repeated motifs prone to α-helicity. The tail domain of transitin contains a motif comprised of more than 50 leucine zipper-like heptad repeats (HR domain) of the consensus sequence LQVEHGD  whereas that of nestin features an 11-amino acid repeat motif whose number of repetitions varies according to the species . Synemin is another type VI IF protein expressed in developing and adult skeletal muscles of both birds and mammals [30–32]. Different studies report that interaction of the long C-terminal tail of synemin with other cytoskeletal components may be a key component linking myofibrillar Z lines to costameres in skeletal muscle cells [33, 34].
The molecular evolution of type VI IF proteins remains poorly studied. As already mentioned, the common denominator shared by all IF proteins is the presence of an α-helical region involved in filament assembly. Two prototypes of cytoplasmic IF proteins, defined by the presence or absence of a long lamin-like coil 1b within the α-helical domain, seem to parallel metazoan phylogeny. The first prototype has the long coil 1b subdomain and often a lamin homology segment in its tail domain. It has been documented for 12 protostomic phyla [35, 36] and an hemichordate, although the "long" coil 1b is shortened by 11 residues in the latter . The second prototype, restricted to the chordates, contains a coil 1b shortened by 42 residues and lack a lamin homology segment. Following a 42 residue deletion that occured at the origin of the chordate branch, type I-III- IF proteins were established by duplication events and sequence drift. The genes encoding type IV NF proteins have different intron positions than do type I-III genes. They were proposed to be derived from retrotransposition of an intron-less intermediate followed by the acquisition of new introns  but this hypothesis has been recently challenged by the documentation of a fish gene combining type I-III intron positions with type IV intron positions .
To analyze the evolution of genes encoding type VI IF proteins, sequence comparison, BLAST searching, synteny studies and phylogenic analysis were performed with members of this group. This study provides new evidence that tanabin, transitin and nestin are indeed orthologous type VI IF proteins. These proteins possess significant diversity in composition of their long C-terminal tails that likely provides them with different, but specific functions in myogenic and neurogenic cells of developing vertebrate systems. In particular, in silico and in vitro analyses provide evidence that the C-terminal extremity of (avian) transitin, but not that of (mammalian) nestin, contains a repeat domain displaying nucleotide hydrolysis activity.
Results and discussion
1-Overview of type VI IF proteins
The cDNA sequence of tanabin from X. laevis has been published , but the organization of its gene structure is not known. In order to analyze the evolution of type VI IFs, we first determined the exon/intron structure of the tanabin gene of X. tropicalis using JGI portal v.4.1. As tanabin was first described in X. laevis , a BLASTp search was made to determine the putative ortholog of tanabin in X. tropicalis. The protein sequence of tanabin from X. laevis (tanabin-xl) was used as the query sequence in BLASTp searching carried out at the JGI portal against the X. tropicalis genome assembly v4.1. A sequence named fgenesh1_pg.C of 1868 bp was found to be 67% identical to tanabin-xl. Tanabin from X. tropicalis (tanabin-xt) is 1970 amino acids (aa) long and possesses the typical α-helical rod domain of IF proteins and a long C-terminal tail of more than 1400 aa. Tanabin-xl and tanabin-xt share more than 90% sequence similarity in their IF rod domain (data not shown).
Protein sequence identity of the alpha helical rod domain and the C-terminal tail of type VI Ifs. Protein sequences deduced from available sequenced genomes present in NCBI and JGI genome assembly v4.1. were analyzed using BL2SEQ searching on the NCBI server. Sequence identities are presented on the table and --- means that no sequence identity was found in these regions of the proteins. Chicken transitin: X80877, human nestin: NM_006617, tanabin-xt: 186291 and human synemin: CAC83859
Sequence identity(%) Rod domain
Transitin vs Tanabin-xt
Transitin vs Nestin
Tanabin-xt vs Nestin
Transitin vs Synemin
Tanabin-xt vs Synemin
Nestin vs Synemin
To investigate potential relationships among type VI IF proteins, a phylogenetic tree was constructed using a multiple alignment of the entire sequence of known type VI proteins. The sequence of NF-M proteins was also used to examine how closely related type VI IF proteins are to NF proteins. As seen in Fig. 2B, such phylogenetic analysis shows that synemin, transitin, tanabin and nestin are all part of a group that is distinct from the NF-M protein. This correlates with the idea that type VI IF genes are the evolutionary result of a duplication event of an ancestral NF gene and that type VI IF genes then evolved independently from NFs. Transitin and tanabin are probably more closely related to each other than to other type VI IF proteins as suggested by their close phylogenetic proximity. In summary, our analysis indicates that tanabin, transitin and nestin form a branch distinct from NF proteins and they are more closely related to each other than to synemin.
2-Tanabin, transitin and nestin are orthologous proteins
3-ATPase and GTPase activity of the transitin HR domain
ATPase score motif associated with the C-terminal tail of tanabin, transitin and nestin of different species by Conserved domain database analysis on the NCBI server. An ATPase motif was detected in tanabin, transitin and nestin in comparison with the domain architectures available in the Conserved domain database on the NCBI server. The score shown in the table is calculated using PSSM scoring matrix based on protein alignment. The expected value is also given for each alignment and significant E-values for this database searching are considered to be > 10-5. Protein sequences for this analysis were obtained from sequenced genomes available on NCBI and JGI genome assembly v4.1. Tanabin-xt: 186291, chicken transitin: X80877, dog predicted-nestin: XP_547531.2, mouse nestin: NP_057910.3, rat nestin: NP_037119.1 and human nestin: NM_006617
E-value (IF domain)
E-value (ATPase domain)
Tanabin (Xenopus laevis) gi|549051
Transitin (Gallus gallus) gi|45384298
Nestin3 (Canis familiaris) gi|73961547
Nestin3 (Monodelphis domestica) gi|126307847
Nestin3 (Bos taurus) gi|76612380
Nestin (Rattus norvegicus) gi|6981262
Nestin (Mus musculus) gi|50363232
Nestin3 (Macaca mulatta) gi|109017378
Nestin (Homo sapiens) gi|1346682
The SMC and AAA+ proteins contain two nucleotide-binding modules, the Walker A and Walker B motifs , defining a broad superfamily of nucleotide-binding proteins including many ATPases, myosin and numerous kinases . In these proteins, the ATP-binding module is activated by the formation of an oligomeric assembly and drives conformational changes affecting target substrates. The Walker A and B motifs of SMC proteins, which show the highest score with transitin HR domain, are located in the N- and C-terminal extremities of these proteins and are separated by a central domain composed of a hinge sequence flanked by two long coiled-coil motifs . As the bulk of transitin HR domain is predicted to have a coiled-coil structure , it may be anticipated that the HR domain presents ATPase activity at one or both ends. The Walker B signature motif, as decribed by Walker , corresponds to R/KX3GX3Lh4D (h = hybdrophobic and X = any residue) and could loosely match with the sequence R DLQEG HGDL QVEHED located at the N-terminal extremity of the HR domain. In fact, hydrolytic activity has been detected in our ATPase assay using fragment HR1–4, which contains the first 4 repeats of the HR domain. In addition, this domain has been shown to completely disassemble the IF network when overexpressed in avian myoblasts (Guérette et al., submitted). Site-directed mutagenesis is now under way to identify the most important residues for ATP binding and hydrolysis.
4-Conservation of the HR domain in some species
To establish whether sequences similar to the HR domain of chicken transitin could be found in species located in upstream branches of vertebrate evolution, a tBLASTn search of Takifugu rubripes (pufferfish) was made using the entire transitin protein sequence. Genome sequence analysis of T. rubripes did not reveal the presence of a nestin homolog . This may explain why the rod domain of desmin was found by tBLASTn analysis to be the strongest hit to the rod domain of transitin (27% identity). On the other hand, the HR domain of transitin is 22% identical to a retinitis pigmentosa GTPase regulator-like (RPGR-like) protein spanning 555 nt with an E-value of 2e-28. As the protein sequence of tanabin is closely related to transitin, tanabin was used to conduct a second tBLASTn search. Once again, the RGPR-like protein emerged (22% identical) spanning 580 nt with an-E value of 2e-21 to the C-terminal of tanabin. The observations suggest that tanabin and transitin tail domains have evolved from an RPGR-like protein.
5-Model for the evolution of type VI IF proteins
Many lines of evidence based on sequence identity, gene structure, synteny comparison and phylogeny searching point to the conclusion that frog tanabin, chicken transitin and mammalian nestin are orthologous members of the type VI IF proteins. The C-terminal domains of both tanabin and transitin were predicted to have nucleotide hydrolysis activity in silico, and indeed, ATPase activity was measured in vitro within the HR domain of transitin. This domain apparently experienced a fast evolution rate that could have resulted in loss of ATPase activity in mammals.
Known type VI protein sequences
Type VI IF protein sequences used in this study were: chicken transitin [GenBank: X80877], human nestin [GenBank: NM_006617], tanabin-xl [GenBank: M99387], tanabin-xt [JGI: 186291], human synemin [GenBank: CAC83859]. Other protein sequences used in this study were: human NF-M [GenBank: CAA68276], mouse NF-M [GenBank: CAA29127], human desmin [GenBank: NP_001918], mouse desmin [GenBank: NP_034173], and RPGR-like [GenBank: AAG00554].
BLAST, multiple sequence alignment and phylogenic tree analysis
BLASTn, BLASTp, tBLASTn and BL2SEQ searches were performed in NCBI or JGI (in the case of X. tropicalis) databases. Default parameters were used to conduct the searches. Multiple sequence alignments were prepared using CLC workbench version 3.0.1. These multiple sequence alignments were used to create a phylogenic tree with neighbor-joining methods with 100 bootstrap analysis using CLC workbench version 3.0.1 software.
Syntenic relationship identification
Chromosomal locations of nestin and transitin genes were identified using physically-mapped human (build 36.1), mouse (build 35.1), rat (build v3.4) and chicken (build 1.1) genomes. For each species, syntenic genes were located using mapviewer (NCBI). In the case of transitin, as this gene was not located on any chicken chromosome (build 1.1) at the onset of our study, the contig NW_094723.1 containing the transitin gene was used to identify neighboring genes. These genes were later located to chicken chromosome 25 (build 2.1) and then compared with physically mapped human, mouse and rat genomes. To analyze synteny relationships of the transitin HR domain, the contigs containing the human and mouse HR sequences were located on human and mouse chromosomes and the genes surrounding these sequences were positioned and compared with the chicken genome.
Assay of ATPase and GTPase activity
Different fusion proteins were cloned as described previously . Fusion proteins were purified by T7-tag affinity purification (Novagen) or by His-tag Sepharose (Amersham) according to the instructions of the manufacturers. ATPase and GTPase activities were determined using "malachite green phosphate assay kits" from BioAssay Systems. After purification, fusion proteins were dialyzed against Buffer A (50 mM Tris-HCL pH 7.5, 10 mM MgCl2, 100 mM NaCl, 20 mM KCl and 1 mM β-mercaptoethanol) overnight at 4°C and concentrated using Centricon YM-10 (Millipore). Protein concentrations were determined with a Micro BCA Protein Assay kit (Pierce). Fusion proteins (0.04 μg/μl) were incubated in Buffer A with 1 mM ATP or 1 mM GTP at 25°C. Aliquots were taken at different times and mixed with malachite green buffers as described by the manufacturer (BioAssay Systems). After 15 min of incubation, the O.D. at 650 nm was determined using a Multiskan Spectrum spectophotometer (ThermoLabSystems). A standard curve with free phosphate was produced according to the instructions of the manufacturer.
SDS-PAGE and Western blots
A fragment of mouse genomic clone RP2389A3 (gi: 106520665) showing the highest sequence identity to chick transitin HR domain has been amplified by PCR and subcloned in a His-tag containing pET30 expression vector to transform BL21(DE3)pLysS bacteria. The expression of the His-tag-HRM fusion protein was induced by 0.1 mM IPTG and bacterial pellets directly solubilized in electrophoresis sample buffer. The protein samples were resolved by SDS-PAGE and transferred to nitrocellulose membranes as described . For Western blots, the membranes were saturated for 1 hour at room temperature using 1% blocking reagent (Roche Diagnostics). The primary antibody (anti His-tag or mAb VAP-5) was incubated for 1 hour and the secondary antibody for 45 minutes, both at room temperature. The proteins were detected using the BM chemiluminescence kit (Roche Diagnostics).
This work was supported by a grant from the Canadian Institutes of Health Research (CIHR; FRN 72199). D.G. is recipient of a CIHR studentship as part of a Strategic Training Program Grant in genomics (STP-53894) We are grateful to Ms Karine Blais and Mr Julien Trépanier for technical assistance and to Dr Sébastien Michaud (Laval University) for critical reading of the manuscript.
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