An evolutionary roadmap to the microtubule-associated protein MAP Tau

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dc.contributor.authorSuendermann, Frederik
dc.contributor.authorFernandez, Maria-Pilar
dc.contributor.authorMorgan, Reginald O.
dc.description.abstractBackground: 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.
dc.description.sponsorshipDAAD (Deutscher Akademischer Austauschdienst)Deutscher Akademischer Austausch Dienst (DAAD); Ministerio de Educacion y CienciaSpanish GovernmentEuropean Commission [BFU2007-67876]; Principado de Asturias [SV-PA-13-ECOEMP-69, GRUPIN14-097]; Lichtenberg fellowship of the state of Lower Saxony; The work was financed by the DAAD (Deutscher Akademischer Austauschdienst) and performed as part of the IPID (''International Promovieren in Deutschland'') doctoral student exchange program from the University of Osnabruck to the host University of Oviedo where this study was carried out. Spanish grants were from the Ministerio de Educacion y Ciencia REF: (BFU2007-67876) and the Principado de Asturias (SV-PA-13-ECOEMP-69 and GRUPIN14-097). Frederik Sundermann was the recipient of a Lichtenberg fellowship of the state of Lower Saxony. The project was supported with computing time by the HLRN (Norddeutscher Verbund fur Hoch-und Hochstleistungsrechnen) and the UV2000/GPU cluster at the computing center of the University Osnabruck.
dc.relation.ispartofBMC GENOMICS
dc.subjectBiotechnology & Applied Microbiology
dc.subjectDomain architecture
dc.subjectGene phylogeny
dc.subjectGenetics & Heredity
dc.subjectMicrotubule associated protein Tau (MAPT protein, MAPT gene)
dc.subjectMicrotubule binding domain
dc.subjectMolecular evolution
dc.subjectProfile hidden Markov models
dc.subjectSaitohin (STH)
dc.subjectStructure-function prediction
dc.titleAn evolutionary roadmap to the microtubule-associated protein MAP Tau
dc.typejournal article
dc.publisher.placeCAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
dcterms.isPartOf.abbreviationBMC Genomics
dcterms.oaStatusgold, Green Published
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