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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

Display of exon structure, conservation and biophysical properties of MAPT on a potential structural model of human MAPTv6. Exon distribution (a) with red-boxed inset showing a MAPT fragment (602–647 in 776 aa isoform 6) that adopts a more stable helical structure when bound to tubulin [6], pbd:2MZ7; site-specific evolutionary conservation calculated by CONSURF (b); surface maps of hydrophobicity by CHIMERA (c); and surface electric potential from APBS (d) are shown. The predicted model with highest confidence score from I-Tasser was reconstructed by threading template fragments from the Protein Data Bank and ab initio modeling with consideration of steric constraints and low free-energy state. Note that MAPT is an intrinsically disordered protein without fixed constraints on 3D crystal or solution structure [18], so this model is intended mainly as a display platform for the protein physicochemical properties
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Fig5: Display of exon structure, conservation and biophysical properties of MAPT on a potential structural model of human MAPTv6. Exon distribution (a) with red-boxed inset showing a MAPT fragment (602–647 in 776 aa isoform 6) that adopts a more stable helical structure when bound to tubulin [6], pbd:2MZ7; site-specific evolutionary conservation calculated by CONSURF (b); surface maps of hydrophobicity by CHIMERA (c); and surface electric potential from APBS (d) are shown. The predicted model with highest confidence score from I-Tasser was reconstructed by threading template fragments from the Protein Data Bank and ab initio modeling with consideration of steric constraints and low free-energy state. Note that MAPT is an intrinsically disordered protein without fixed constraints on 3D crystal or solution structure [18], so this model is intended mainly as a display platform for the protein physicochemical properties

Mentions: The MAPT primary structure varies among orthologs in the multiple sequence alignments and corresponding pHMMs (Fig. 4) and these data provide a physicochemical basis for prediction of the secondary structure (not shown). However, it is becoming recognized that even a completely disordered 3D structure may adopt distinct regional conformations as a consequence of binding to molecular targets or cellular structures [5, 6, 18]. Despite the current lack of a static 3D crystal structure and difficulty in visualizing dynamic simulations from NMR solution structure or in silico modeling, we estimated one out of many possible 3D structures of full-length MAPT based on fragment template threading with steric and energy constraints using I-Tasser v4.1 [44]. The highest scoring model 1 described a fully coiled protein essentially without α-helices nor β-strands. We incorporated specific types of other information into this structure, such as exon distribution (Fig. 5a), site-specific residue conservation (Fig. 5b), hydrophobicity map (Fig. 5c) and electric charge distribution (Fig. 5d).Fig. 5


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

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

Display of exon structure, conservation and biophysical properties of MAPT on a potential structural model of human MAPTv6. Exon distribution (a) with red-boxed inset showing a MAPT fragment (602–647 in 776 aa isoform 6) that adopts a more stable helical structure when bound to tubulin [6], pbd:2MZ7; site-specific evolutionary conservation calculated by CONSURF (b); surface maps of hydrophobicity by CHIMERA (c); and surface electric potential from APBS (d) are shown. The predicted model with highest confidence score from I-Tasser was reconstructed by threading template fragments from the Protein Data Bank and ab initio modeling with consideration of steric constraints and low free-energy state. Note that MAPT is an intrinsically disordered protein without fixed constraints on 3D crystal or solution structure [18], so this model is intended mainly as a display platform for the protein physicochemical properties
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: Display of exon structure, conservation and biophysical properties of MAPT on a potential structural model of human MAPTv6. Exon distribution (a) with red-boxed inset showing a MAPT fragment (602–647 in 776 aa isoform 6) that adopts a more stable helical structure when bound to tubulin [6], pbd:2MZ7; site-specific evolutionary conservation calculated by CONSURF (b); surface maps of hydrophobicity by CHIMERA (c); and surface electric potential from APBS (d) are shown. The predicted model with highest confidence score from I-Tasser was reconstructed by threading template fragments from the Protein Data Bank and ab initio modeling with consideration of steric constraints and low free-energy state. Note that MAPT is an intrinsically disordered protein without fixed constraints on 3D crystal or solution structure [18], so this model is intended mainly as a display platform for the protein physicochemical properties
Mentions: The MAPT primary structure varies among orthologs in the multiple sequence alignments and corresponding pHMMs (Fig. 4) and these data provide a physicochemical basis for prediction of the secondary structure (not shown). However, it is becoming recognized that even a completely disordered 3D structure may adopt distinct regional conformations as a consequence of binding to molecular targets or cellular structures [5, 6, 18]. Despite the current lack of a static 3D crystal structure and difficulty in visualizing dynamic simulations from NMR solution structure or in silico modeling, we estimated one out of many possible 3D structures of full-length MAPT based on fragment template threading with steric and energy constraints using I-Tasser v4.1 [44]. The highest scoring model 1 described a fully coiled protein essentially without α-helices nor β-strands. We incorporated specific types of other information into this structure, such as exon distribution (Fig. 5a), site-specific residue conservation (Fig. 5b), hydrophobicity map (Fig. 5c) and electric charge distribution (Fig. 5d).Fig. 5

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