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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 pHMM sequence logo of the 4 microtubule binding domains in the 3 protein subfamilies MAPT, MAP2 and MAP4. More than 1200 individual MTBDs were aligned to build a pHMM and saved as sequence logo in scalar vector graphics format. The interpretation of amino acid distributions and column heights is summarized in Fig. 4 legend. Those sites characterized by Z-scores from SDPPRED as having distinct but conserved aa between the 4 different MTBDs in 3 paralogous subfamilies of a subclassified alignment of the 1200 domains, are shaded and starred as “specificity determining positions” responsible for functional divergence. b The 12 individual subfamily logos enable a direct comparison of all MTBD molecular profiles. The aa replacement of Ile/Val for Cys in the core tubulin binding motif “KCGS” of domains 2 and 3 was the most significant (Z-score 4.64 in A) specificity determining site (starred) and the deletion at position 12 in domains 1–3 differentiates these from domain 4. c SDP sequence logos of 5 sites in MTBD subalignments of 100+ proteins each with the highest Z-scores from SDP-PRED analysis. d Maximum likelihood analysis of the 12 MTBD subalignments of 100+ proteins each (using RAxML, WAG substitution model, 100 bootstrap pseudoalignments and gamma rates with alpha = 1.3). The point of separation of domains 1 and 4 from 2 and 3 was based on a midpoint root reflecting in the evolutionary relatedness of these domain pairs. Modest boostrap values were a consequence of the short, 33-aa sequence length and the triangle fans represent 100+ species orthologs for each MTBD category. e The influence of extreme cold adaptation on MAPT in the Antarctic rockcod Notothenia coriiceps was determined by reconstructing the transcript and deduced protein sequence from the corresponding genome assembly (gb:KL666590.1). The results showed 7 sequential MTBDs identified by their match score E-value to individual pHMMs (B above) with a 4-fold tandem duplication of MTBD 2 containing the typical central Cys preceded by an aa replacement from Lys to Arg
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Fig3: a pHMM sequence logo of the 4 microtubule binding domains in the 3 protein subfamilies MAPT, MAP2 and MAP4. More than 1200 individual MTBDs were aligned to build a pHMM and saved as sequence logo in scalar vector graphics format. The interpretation of amino acid distributions and column heights is summarized in Fig. 4 legend. Those sites characterized by Z-scores from SDPPRED as having distinct but conserved aa between the 4 different MTBDs in 3 paralogous subfamilies of a subclassified alignment of the 1200 domains, are shaded and starred as “specificity determining positions” responsible for functional divergence. b The 12 individual subfamily logos enable a direct comparison of all MTBD molecular profiles. The aa replacement of Ile/Val for Cys in the core tubulin binding motif “KCGS” of domains 2 and 3 was the most significant (Z-score 4.64 in A) specificity determining site (starred) and the deletion at position 12 in domains 1–3 differentiates these from domain 4. c SDP sequence logos of 5 sites in MTBD subalignments of 100+ proteins each with the highest Z-scores from SDP-PRED analysis. d Maximum likelihood analysis of the 12 MTBD subalignments of 100+ proteins each (using RAxML, WAG substitution model, 100 bootstrap pseudoalignments and gamma rates with alpha = 1.3). The point of separation of domains 1 and 4 from 2 and 3 was based on a midpoint root reflecting in the evolutionary relatedness of these domain pairs. Modest boostrap values were a consequence of the short, 33-aa sequence length and the triangle fans represent 100+ species orthologs for each MTBD category. e The influence of extreme cold adaptation on MAPT in the Antarctic rockcod Notothenia coriiceps was determined by reconstructing the transcript and deduced protein sequence from the corresponding genome assembly (gb:KL666590.1). The results showed 7 sequential MTBDs identified by their match score E-value to individual pHMMs (B above) with a 4-fold tandem duplication of MTBD 2 containing the typical central Cys preceded by an aa replacement from Lys to Arg

Mentions: Our next aim was to define those sites likely to be responsible for the functional divergence between the paralogous families MAPT, MAP2 and MAP4 and within the MTBDs. This issue was addressed by examining the region containing the 4 well-conserved MTBDs in these subfamilies with programs such as SDPclust or SDPfox [35] that measure both the level of amino acid conservation at each site and the significance of any conserved changes (i.e. aa replacements) characteristic of paralogous divergence. A composite pHMM logo of 1200 MTBDs compiled in our studies (Fig. 3a) highlighted the core motif “KxGS” responsible for microtubule binding and the lesser prominence of the initial 6 aa of domains 2 and 3 implicated in paired helical filament (PHF) tangling of MAPT neuronal aggregates [10, 36]. A clustered alignment of the 4 individual MTBDs in the 3 subfamilies produced 12 defining logos that revealed isolated differences between these otherwise homologous domains (Fig. 3b) and scored those conserved sites that differed most significantly between the 12 classes. Figure 3a identified these divergent sites by Z-scores and stars while Fig. 3b highlighted the individual changes as gold-shaded residues. Noteworthy differences include the greater number of conserved prolines in domains 1, the conserved Cys in core domains 2 and 3 and the increase of acidic residues in domains 4. The replacement of I/V at positions 17–18 of MTBD repeats 1 and 4 with a prominent Cys residue in MTBD repeats 2 and 3 is a particularly significant change likely to be associated with differences in microtubule binding kinetics of the separate domains [36, 37]. The 5 highest scoring differences were summarized in Fig. 3c to delineate the conserved residues and/or changes at these informative positions 8,10,11,15,18 and a Maximum Likelihood tree of all 1200 MTBDs (Fig. 3d) supported the functionally divergent segregation of MTBDs 1 and 4 from 2 and 3 albeit with modest bootstrap support due to the shortness of the region analyzed (33 aa from 1200 MTBDs). The evolution of this domain may have introduced an alignment gap at position 12 in MTBDs 1, 2, 3 or insertion in MTBD 4 contributing to the divergence of the 3 subfamily members.Fig. 3


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

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

a pHMM sequence logo of the 4 microtubule binding domains in the 3 protein subfamilies MAPT, MAP2 and MAP4. More than 1200 individual MTBDs were aligned to build a pHMM and saved as sequence logo in scalar vector graphics format. The interpretation of amino acid distributions and column heights is summarized in Fig. 4 legend. Those sites characterized by Z-scores from SDPPRED as having distinct but conserved aa between the 4 different MTBDs in 3 paralogous subfamilies of a subclassified alignment of the 1200 domains, are shaded and starred as “specificity determining positions” responsible for functional divergence. b The 12 individual subfamily logos enable a direct comparison of all MTBD molecular profiles. The aa replacement of Ile/Val for Cys in the core tubulin binding motif “KCGS” of domains 2 and 3 was the most significant (Z-score 4.64 in A) specificity determining site (starred) and the deletion at position 12 in domains 1–3 differentiates these from domain 4. c SDP sequence logos of 5 sites in MTBD subalignments of 100+ proteins each with the highest Z-scores from SDP-PRED analysis. d Maximum likelihood analysis of the 12 MTBD subalignments of 100+ proteins each (using RAxML, WAG substitution model, 100 bootstrap pseudoalignments and gamma rates with alpha = 1.3). The point of separation of domains 1 and 4 from 2 and 3 was based on a midpoint root reflecting in the evolutionary relatedness of these domain pairs. Modest boostrap values were a consequence of the short, 33-aa sequence length and the triangle fans represent 100+ species orthologs for each MTBD category. e The influence of extreme cold adaptation on MAPT in the Antarctic rockcod Notothenia coriiceps was determined by reconstructing the transcript and deduced protein sequence from the corresponding genome assembly (gb:KL666590.1). The results showed 7 sequential MTBDs identified by their match score E-value to individual pHMMs (B above) with a 4-fold tandem duplication of MTBD 2 containing the typical central Cys preceded by an aa replacement from Lys to Arg
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: a pHMM sequence logo of the 4 microtubule binding domains in the 3 protein subfamilies MAPT, MAP2 and MAP4. More than 1200 individual MTBDs were aligned to build a pHMM and saved as sequence logo in scalar vector graphics format. The interpretation of amino acid distributions and column heights is summarized in Fig. 4 legend. Those sites characterized by Z-scores from SDPPRED as having distinct but conserved aa between the 4 different MTBDs in 3 paralogous subfamilies of a subclassified alignment of the 1200 domains, are shaded and starred as “specificity determining positions” responsible for functional divergence. b The 12 individual subfamily logos enable a direct comparison of all MTBD molecular profiles. The aa replacement of Ile/Val for Cys in the core tubulin binding motif “KCGS” of domains 2 and 3 was the most significant (Z-score 4.64 in A) specificity determining site (starred) and the deletion at position 12 in domains 1–3 differentiates these from domain 4. c SDP sequence logos of 5 sites in MTBD subalignments of 100+ proteins each with the highest Z-scores from SDP-PRED analysis. d Maximum likelihood analysis of the 12 MTBD subalignments of 100+ proteins each (using RAxML, WAG substitution model, 100 bootstrap pseudoalignments and gamma rates with alpha = 1.3). The point of separation of domains 1 and 4 from 2 and 3 was based on a midpoint root reflecting in the evolutionary relatedness of these domain pairs. Modest boostrap values were a consequence of the short, 33-aa sequence length and the triangle fans represent 100+ species orthologs for each MTBD category. e The influence of extreme cold adaptation on MAPT in the Antarctic rockcod Notothenia coriiceps was determined by reconstructing the transcript and deduced protein sequence from the corresponding genome assembly (gb:KL666590.1). The results showed 7 sequential MTBDs identified by their match score E-value to individual pHMMs (B above) with a 4-fold tandem duplication of MTBD 2 containing the typical central Cys preceded by an aa replacement from Lys to Arg
Mentions: Our next aim was to define those sites likely to be responsible for the functional divergence between the paralogous families MAPT, MAP2 and MAP4 and within the MTBDs. This issue was addressed by examining the region containing the 4 well-conserved MTBDs in these subfamilies with programs such as SDPclust or SDPfox [35] that measure both the level of amino acid conservation at each site and the significance of any conserved changes (i.e. aa replacements) characteristic of paralogous divergence. A composite pHMM logo of 1200 MTBDs compiled in our studies (Fig. 3a) highlighted the core motif “KxGS” responsible for microtubule binding and the lesser prominence of the initial 6 aa of domains 2 and 3 implicated in paired helical filament (PHF) tangling of MAPT neuronal aggregates [10, 36]. A clustered alignment of the 4 individual MTBDs in the 3 subfamilies produced 12 defining logos that revealed isolated differences between these otherwise homologous domains (Fig. 3b) and scored those conserved sites that differed most significantly between the 12 classes. Figure 3a identified these divergent sites by Z-scores and stars while Fig. 3b highlighted the individual changes as gold-shaded residues. Noteworthy differences include the greater number of conserved prolines in domains 1, the conserved Cys in core domains 2 and 3 and the increase of acidic residues in domains 4. The replacement of I/V at positions 17–18 of MTBD repeats 1 and 4 with a prominent Cys residue in MTBD repeats 2 and 3 is a particularly significant change likely to be associated with differences in microtubule binding kinetics of the separate domains [36, 37]. The 5 highest scoring differences were summarized in Fig. 3c to delineate the conserved residues and/or changes at these informative positions 8,10,11,15,18 and a Maximum Likelihood tree of all 1200 MTBDs (Fig. 3d) supported the functionally divergent segregation of MTBDs 1 and 4 from 2 and 3 albeit with modest bootstrap support due to the shortness of the region analyzed (33 aa from 1200 MTBDs). The evolution of this domain may have introduced an alignment gap at position 12 in MTBDs 1, 2, 3 or insertion in MTBD 4 contributing to the divergence of the 3 subfamily members.Fig. 3

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