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 Alignment pHMM logo for coding exons from full-length vertebrate MAPT homologs. The profile was reconstructed by SKYLIGN from a hidden Markov model based on a protein alignment of 117 orthologs validated by phylogenetic analysis. Exon numbers and lengths in amino acids and nucleotides are indicated with intron insertion phase numbers at exon junctures. Each site shows the relative proportion of 20 possible amino acids above background level (observed or hidden) and the total column height reflects the information content at each site, based on the overall conservation level imposed by functional constraint. Known MTBDs in exons 11–14 are grey shaded and sites inferred to possess some functional role (known or unknown) are shaded in red to emphasize their elevated column height conservation. The legend at the lower right summarizes other documented sequence features such as nonsynonymous population variants (inverted triangles), post-translational modifications (P-phosphorylation or A-acetylation) and specificity determining Cys residues (yellow stars). b Mammalian subHMM matches projected on a linear 776 aa human MAPT sequence. Each class is represented as a ribbon plot and each subHMM match is color-coded by the HHsearch match probability. The position of the match is indicated relative to the human sequence. The functional organization of tau is indicated on top similar to Fig. 1c. The single subHMMs are indicated in Roman numbers and the pHMM logos are displayed in Additional file 4: Figure S4
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: a Alignment pHMM logo for coding exons from full-length vertebrate MAPT homologs. The profile was reconstructed by SKYLIGN from a hidden Markov model based on a protein alignment of 117 orthologs validated by phylogenetic analysis. Exon numbers and lengths in amino acids and nucleotides are indicated with intron insertion phase numbers at exon junctures. Each site shows the relative proportion of 20 possible amino acids above background level (observed or hidden) and the total column height reflects the information content at each site, based on the overall conservation level imposed by functional constraint. Known MTBDs in exons 11–14 are grey shaded and sites inferred to possess some functional role (known or unknown) are shaded in red to emphasize their elevated column height conservation. The legend at the lower right summarizes other documented sequence features such as nonsynonymous population variants (inverted triangles), post-translational modifications (P-phosphorylation or A-acetylation) and specificity determining Cys residues (yellow stars). b Mammalian subHMM matches projected on a linear 776 aa human MAPT sequence. Each class is represented as a ribbon plot and each subHMM match is color-coded by the HHsearch match probability. The position of the match is indicated relative to the human sequence. The functional organization of tau is indicated on top similar to Fig. 1c. The single subHMMs are indicated in Roman numbers and the pHMM logos are displayed in Additional file 4: Figure S4

Mentions: The relatively low sequence identity/similarity of MAP amino terminal projections and central domains could benefit from computational phylogenetic and statistical HMM analyses of a more extensive species range to validate conserved regions of functional importance and sites responsible for functional divergence. The need for accurate, extensive alignments of true homologs to resolve phylogenetic analyses and yield informative molecular profiles of functional regions implicitly demands full-length protein sequences based on all exons from the broadest range of species possible. Intrinsically disordered proteins commonly have multiple interaction partners, exemplified by the >16 high confidence, experimentally determined binding partners for MAPT in the STRING protein interaction database [32]. While attention has naturally focused on the C-terminal MTBD [18], the amino terminal projection domain may also undergo entropic repulsion [33] or electrostatic attraction (see later Results, Fig. 4d) or more specific, ligand-based interactions dependent on conformational changes yet to be defined. The aim of tracing the evolutionary origins and relationships between MAPs and classifying the most distant homologs in early-diverging vertebrates thus required primary reconstruction and annotation of many novel MAP homologs, followed by the application of pHMM models for individual missing exons and full-length transcripts to verify new members. Homologs were culled by PSI-BLAST and JACKHMMER searches of public sequence databases at the National Center for Biotechnology Information (NCBI) and UniProtKB, while those not yet catalogued in public databases were deduced and completed from recently sequenced genomes of mammals, reptiles (turtles, lizards and crocodiles), birds, amphibians and fishes [25, 34]. The latter included coelacanth, spotted gar and ray-finned teleosts such as the Antarctic icefish Notothenia coriiceps, cartilagenous fishes (sharks, rays and skates) and jawless fishes (lampreys, hagfish) in order to span all classes of extant vertebrates.


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

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

a Alignment pHMM logo for coding exons from full-length vertebrate MAPT homologs. The profile was reconstructed by SKYLIGN from a hidden Markov model based on a protein alignment of 117 orthologs validated by phylogenetic analysis. Exon numbers and lengths in amino acids and nucleotides are indicated with intron insertion phase numbers at exon junctures. Each site shows the relative proportion of 20 possible amino acids above background level (observed or hidden) and the total column height reflects the information content at each site, based on the overall conservation level imposed by functional constraint. Known MTBDs in exons 11–14 are grey shaded and sites inferred to possess some functional role (known or unknown) are shaded in red to emphasize their elevated column height conservation. The legend at the lower right summarizes other documented sequence features such as nonsynonymous population variants (inverted triangles), post-translational modifications (P-phosphorylation or A-acetylation) and specificity determining Cys residues (yellow stars). b Mammalian subHMM matches projected on a linear 776 aa human MAPT sequence. Each class is represented as a ribbon plot and each subHMM match is color-coded by the HHsearch match probability. The position of the match is indicated relative to the human sequence. The functional organization of tau is indicated on top similar to Fig. 1c. The single subHMMs are indicated in Roman numbers and the pHMM logos are displayed in Additional file 4: Figure S4
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: a Alignment pHMM logo for coding exons from full-length vertebrate MAPT homologs. The profile was reconstructed by SKYLIGN from a hidden Markov model based on a protein alignment of 117 orthologs validated by phylogenetic analysis. Exon numbers and lengths in amino acids and nucleotides are indicated with intron insertion phase numbers at exon junctures. Each site shows the relative proportion of 20 possible amino acids above background level (observed or hidden) and the total column height reflects the information content at each site, based on the overall conservation level imposed by functional constraint. Known MTBDs in exons 11–14 are grey shaded and sites inferred to possess some functional role (known or unknown) are shaded in red to emphasize their elevated column height conservation. The legend at the lower right summarizes other documented sequence features such as nonsynonymous population variants (inverted triangles), post-translational modifications (P-phosphorylation or A-acetylation) and specificity determining Cys residues (yellow stars). b Mammalian subHMM matches projected on a linear 776 aa human MAPT sequence. Each class is represented as a ribbon plot and each subHMM match is color-coded by the HHsearch match probability. The position of the match is indicated relative to the human sequence. The functional organization of tau is indicated on top similar to Fig. 1c. The single subHMMs are indicated in Roman numbers and the pHMM logos are displayed in Additional file 4: Figure S4
Mentions: The relatively low sequence identity/similarity of MAP amino terminal projections and central domains could benefit from computational phylogenetic and statistical HMM analyses of a more extensive species range to validate conserved regions of functional importance and sites responsible for functional divergence. The need for accurate, extensive alignments of true homologs to resolve phylogenetic analyses and yield informative molecular profiles of functional regions implicitly demands full-length protein sequences based on all exons from the broadest range of species possible. Intrinsically disordered proteins commonly have multiple interaction partners, exemplified by the >16 high confidence, experimentally determined binding partners for MAPT in the STRING protein interaction database [32]. While attention has naturally focused on the C-terminal MTBD [18], the amino terminal projection domain may also undergo entropic repulsion [33] or electrostatic attraction (see later Results, Fig. 4d) or more specific, ligand-based interactions dependent on conformational changes yet to be defined. The aim of tracing the evolutionary origins and relationships between MAPs and classifying the most distant homologs in early-diverging vertebrates thus required primary reconstruction and annotation of many novel MAP homologs, followed by the application of pHMM models for individual missing exons and full-length transcripts to verify new members. Homologs were culled by PSI-BLAST and JACKHMMER searches of public sequence databases at the National Center for Biotechnology Information (NCBI) and UniProtKB, while those not yet catalogued in public databases were deduced and completed from recently sequenced genomes of mammals, reptiles (turtles, lizards and crocodiles), birds, amphibians and fishes [25, 34]. The latter included coelacanth, spotted gar and ray-finned teleosts such as the Antarctic icefish Notothenia coriiceps, cartilagenous fishes (sharks, rays and skates) and jawless fishes (lampreys, hagfish) in order to span all classes of extant vertebrates.

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