Limits...
An evolutionary roadmap to the microtubule-associated protein MAP Tau.

Sündermann F, Fernandez MP, Morgan RO - BMC Genomics (2016)

Bottom Line: The microtubule associated protein Tau (MAPT) promotes assembly and interaction of microtubules with the cytoskeleton, impinging on axonal transport and synaptic plasticity.These analyses clarified ambiguities of MAPT nomenclature, defined the order, timing and pattern of its molecular evolution and identified key residues and motifs relevant to its protein interaction properties and pathogenic role.Additional unexpected findings included the expansion of cysteine-containing, microtubule binding domains of MAPT in cold adapted Antarctic icefish and the emergence of a novel multiexonic saitohin (STH) gene from repetitive elements in MAPT intron 11 of certain primate genomes.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, University of Osnabrück, Osnabrück, Germany.

ABSTRACT

Background: The microtubule associated protein Tau (MAPT) promotes assembly and interaction of microtubules with the cytoskeleton, impinging on axonal transport and synaptic plasticity. Its neuronal expression and intrinsic disorder implicate it in some 30 tauopathies such as Alzheimer's disease and frontotemporal dementia. These pathophysiological studies have yet to be complemented by computational analyses of its molecular evolution and structural models of all its functional domains to explain the molecular basis for its conservation profile, its site-specific interactions and the propensity to conformational disorder and aggregate formation.

Results: We systematically annotated public sequence data to reconstruct unspliced MAPT, MAP2 and MAP4 transcripts spanning all represented genomes. Bayesian and maximum likelihood phylogenetic analyses, genetic linkage maps and domain architectures distinguished a nonvertebrate outgroup from the emergence of MAP4 and its subsequent ancestral duplication to MAP2 and MAPT. These events were coupled to other linked genes such as KANSL1L and KANSL and may thus be consequent to large-scale chromosomal duplications originating in the extant vertebrate genomes of hagfish and lamprey. Profile hidden Markov models (pHMMs), clustered subalignments and 3D structural predictions defined potential interaction motifs and specificity determining sites to reveal distinct signatures between the four homologous microtubule binding domains and independent divergence of the amino terminus.

Conclusion: These analyses clarified ambiguities of MAPT nomenclature, defined the order, timing and pattern of its molecular evolution and identified key residues and motifs relevant to its protein interaction properties and pathogenic role. Additional unexpected findings included the expansion of cysteine-containing, microtubule binding domains of MAPT in cold adapted Antarctic icefish and the emergence of a novel multiexonic saitohin (STH) gene from repetitive elements in MAPT intron 11 of certain primate genomes.

No MeSH data available.


Related in: MedlinePlus

a Bayesian consensus phylogenetic tree of the MAPT/MAP2/MAP4 family. Putative homologous proteins of MAPT, MAP2 and MAP4 were retrieved from the NCBI-GenPept and UniProt databases and either completed or reconstructed ab initio by manual curation from BLAST and HMMER comparisons of genome assembly and coding transcript sequences. Full-length proteins representing the full species range for each vertebrate subfamily and a nonvertebrate outgroup were aligned (1947 aa from 102 species) and analyzed to consensus with ExaBayes on the Hanover supercomputer. Posterior probabilities and ML bootstrap percentage confidence values (in brackets) for the branching topology are shown at the nodes and branch lengths (SBL 63.9) are proportional to the amount of evolution along the horizontal scale (non-linear time). The branching topology was well supported and conformed to the known species divergence order identified by taxon symbols and descriptive labels. b Protein domain architectures (MTBD) representative of the vertebrate subfamilies were observed to contrast with various nonvertebrate homologs included in the phylogenetic analysis
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4815063&req=5

Fig2: a Bayesian consensus phylogenetic tree of the MAPT/MAP2/MAP4 family. Putative homologous proteins of MAPT, MAP2 and MAP4 were retrieved from the NCBI-GenPept and UniProt databases and either completed or reconstructed ab initio by manual curation from BLAST and HMMER comparisons of genome assembly and coding transcript sequences. Full-length proteins representing the full species range for each vertebrate subfamily and a nonvertebrate outgroup were aligned (1947 aa from 102 species) and analyzed to consensus with ExaBayes on the Hanover supercomputer. Posterior probabilities and ML bootstrap percentage confidence values (in brackets) for the branching topology are shown at the nodes and branch lengths (SBL 63.9) are proportional to the amount of evolution along the horizontal scale (non-linear time). The branching topology was well supported and conformed to the known species divergence order identified by taxon symbols and descriptive labels. b Protein domain architectures (MTBD) representative of the vertebrate subfamilies were observed to contrast with various nonvertebrate homologs included in the phylogenetic analysis

Mentions: Maximum likelihood analysis by RAxML, ExaML and MEGA of an alignment with 1949 sites in 102 species established the emergence of MAP4 from a metazoan ancestor and this was confirmed by the Bayesian consensus tree from ExaBayes with congruent topology and superior confidence values (Fig. 2). Worm, mollusc, insect and urchin MAPs exhibit similar domain architectures with shorter amino termini, while the tunicate Ciona intestinalis and fungus Rhizopus delemar are distinct (Fig. 2b). MAP4 was therefore considered to originate in the earliest vertebrates (hagfish and lampreys) and subsequent duplication of a more evolved common ancestor led to the formation of MAPT and MAP2 as sister genes. With this in mind, the strong evidence for MAPT full-length orthologs in hagfish and lamprey implied that MAP2 should be present in these same species; hence it is noteworthy that the lamprey branches for “short fragments” near the base of Fig. 2a were indeed recognized as MAP2 orthologs by the most significant matches of HMMSCAN to the pHMM digital template of MAP2. Bootstrap support at most bifurcations was highly significant in Maximum Likelihood, Neighbor-Joining and Bayesian posterior probability analyses. A more comprehensive dataset consisting of 2029 positions for 292 sequences was similarly analyzed by RAxML and ExaML (Additional file 1: Figure S1) to corroborate the results in greater detail, confirming the expected order of intermediate species with consistent branch lengths and, especially, the orderly separation of MAP4, MAP2 and MAPT in early vertebrates.Fig. 2


An evolutionary roadmap to the microtubule-associated protein MAP Tau.

Sündermann F, Fernandez MP, Morgan RO - BMC Genomics (2016)

a Bayesian consensus phylogenetic tree of the MAPT/MAP2/MAP4 family. Putative homologous proteins of MAPT, MAP2 and MAP4 were retrieved from the NCBI-GenPept and UniProt databases and either completed or reconstructed ab initio by manual curation from BLAST and HMMER comparisons of genome assembly and coding transcript sequences. Full-length proteins representing the full species range for each vertebrate subfamily and a nonvertebrate outgroup were aligned (1947 aa from 102 species) and analyzed to consensus with ExaBayes on the Hanover supercomputer. Posterior probabilities and ML bootstrap percentage confidence values (in brackets) for the branching topology are shown at the nodes and branch lengths (SBL 63.9) are proportional to the amount of evolution along the horizontal scale (non-linear time). The branching topology was well supported and conformed to the known species divergence order identified by taxon symbols and descriptive labels. b Protein domain architectures (MTBD) representative of the vertebrate subfamilies were observed to contrast with various nonvertebrate homologs included in the phylogenetic analysis
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4815063&req=5

Fig2: a Bayesian consensus phylogenetic tree of the MAPT/MAP2/MAP4 family. Putative homologous proteins of MAPT, MAP2 and MAP4 were retrieved from the NCBI-GenPept and UniProt databases and either completed or reconstructed ab initio by manual curation from BLAST and HMMER comparisons of genome assembly and coding transcript sequences. Full-length proteins representing the full species range for each vertebrate subfamily and a nonvertebrate outgroup were aligned (1947 aa from 102 species) and analyzed to consensus with ExaBayes on the Hanover supercomputer. Posterior probabilities and ML bootstrap percentage confidence values (in brackets) for the branching topology are shown at the nodes and branch lengths (SBL 63.9) are proportional to the amount of evolution along the horizontal scale (non-linear time). The branching topology was well supported and conformed to the known species divergence order identified by taxon symbols and descriptive labels. b Protein domain architectures (MTBD) representative of the vertebrate subfamilies were observed to contrast with various nonvertebrate homologs included in the phylogenetic analysis
Mentions: Maximum likelihood analysis by RAxML, ExaML and MEGA of an alignment with 1949 sites in 102 species established the emergence of MAP4 from a metazoan ancestor and this was confirmed by the Bayesian consensus tree from ExaBayes with congruent topology and superior confidence values (Fig. 2). Worm, mollusc, insect and urchin MAPs exhibit similar domain architectures with shorter amino termini, while the tunicate Ciona intestinalis and fungus Rhizopus delemar are distinct (Fig. 2b). MAP4 was therefore considered to originate in the earliest vertebrates (hagfish and lampreys) and subsequent duplication of a more evolved common ancestor led to the formation of MAPT and MAP2 as sister genes. With this in mind, the strong evidence for MAPT full-length orthologs in hagfish and lamprey implied that MAP2 should be present in these same species; hence it is noteworthy that the lamprey branches for “short fragments” near the base of Fig. 2a were indeed recognized as MAP2 orthologs by the most significant matches of HMMSCAN to the pHMM digital template of MAP2. Bootstrap support at most bifurcations was highly significant in Maximum Likelihood, Neighbor-Joining and Bayesian posterior probability analyses. A more comprehensive dataset consisting of 2029 positions for 292 sequences was similarly analyzed by RAxML and ExaML (Additional file 1: Figure S1) to corroborate the results in greater detail, confirming the expected order of intermediate species with consistent branch lengths and, especially, the orderly separation of MAP4, MAP2 and MAPT in early vertebrates.Fig. 2

Bottom Line: The microtubule associated protein Tau (MAPT) promotes assembly and interaction of microtubules with the cytoskeleton, impinging on axonal transport and synaptic plasticity.These analyses clarified ambiguities of MAPT nomenclature, defined the order, timing and pattern of its molecular evolution and identified key residues and motifs relevant to its protein interaction properties and pathogenic role.Additional unexpected findings included the expansion of cysteine-containing, microtubule binding domains of MAPT in cold adapted Antarctic icefish and the emergence of a novel multiexonic saitohin (STH) gene from repetitive elements in MAPT intron 11 of certain primate genomes.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, University of Osnabrück, Osnabrück, Germany.

ABSTRACT

Background: The microtubule associated protein Tau (MAPT) promotes assembly and interaction of microtubules with the cytoskeleton, impinging on axonal transport and synaptic plasticity. Its neuronal expression and intrinsic disorder implicate it in some 30 tauopathies such as Alzheimer's disease and frontotemporal dementia. These pathophysiological studies have yet to be complemented by computational analyses of its molecular evolution and structural models of all its functional domains to explain the molecular basis for its conservation profile, its site-specific interactions and the propensity to conformational disorder and aggregate formation.

Results: We systematically annotated public sequence data to reconstruct unspliced MAPT, MAP2 and MAP4 transcripts spanning all represented genomes. Bayesian and maximum likelihood phylogenetic analyses, genetic linkage maps and domain architectures distinguished a nonvertebrate outgroup from the emergence of MAP4 and its subsequent ancestral duplication to MAP2 and MAPT. These events were coupled to other linked genes such as KANSL1L and KANSL and may thus be consequent to large-scale chromosomal duplications originating in the extant vertebrate genomes of hagfish and lamprey. Profile hidden Markov models (pHMMs), clustered subalignments and 3D structural predictions defined potential interaction motifs and specificity determining sites to reveal distinct signatures between the four homologous microtubule binding domains and independent divergence of the amino terminus.

Conclusion: These analyses clarified ambiguities of MAPT nomenclature, defined the order, timing and pattern of its molecular evolution and identified key residues and motifs relevant to its protein interaction properties and pathogenic role. Additional unexpected findings included the expansion of cysteine-containing, microtubule binding domains of MAPT in cold adapted Antarctic icefish and the emergence of a novel multiexonic saitohin (STH) gene from repetitive elements in MAPT intron 11 of certain primate genomes.

No MeSH data available.


Related in: MedlinePlus