An evolutionary roadmap to the microtubule-associated protein MAP Tau

Sündermann et al. BMC Genomics (2016) 17:264 DOI 10.1186/s12864-016-2590-9 RESEARCH ARTICLE Open Access An evolutionary roadmap to the microtubule-associated protein MAP Tau Frederik Sündermann1, Maria-Pilar Fernandez2 and Reginald O. Morgan2* 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. Keywords: Microtubule associated protein Tau (MAPT protein, MAPT gene), Microtubule binding domain, Gene phylogeny, Molecular evolution, Profile hidden Markov models, Saitohin (STH), Domain architecture, Structure-function prediction Background The microtubule associated protein Tau (MAPT) belongs to a family of homologous proteins, including MAP2 and MAP4, with 3 or 4 basic microtubule binding domains (MTBDs) in their carboxy terminal regions. The amino terminus may also interact with microtubules but precise functional interactions are poorly understood [1]. The 3 members of the MAPT/MAP2/MAP4 family are expressed as multiple splice variants, some of which contain different numbers of MTBDs [2]. MAPT and MAP2 are expressed * Correspondence: 2 Department of Biochemistry and Molecular Biology, Edificio Santiago Gascon 4.3, Faculty of Medicine, University of Oviedo, 33006 Oviedo, Spain Full list of author information is available at the end of the article mainly in neurons where they show a characteristic subcellular compartmentalization, with MAP2 being somatodendritic, MAPT predominantly present in the axon and MAP4 a major non-neuronal MAP. MAPT is a natively disordered protein which can adopt dynamic conformations [3]. Intrinsically disordered proteins account for a substantial proportion of the proteome and many of them are promiscuous binders that undergo a partial transition to a more ordered state in which they interact stably with various partners and frequently function as molecular hubs in protein interaction networks [4–6]. Primary and posttranslational modifications of MAPT can compromise its physiological role in microtubule assembly and in mediating other cellular © 2016 Sündermann et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sündermann et al. BMC Genomics (2016) 17:264 functions [7–10]. They might also contribute to aggregate formation in central neurons that are pathognomonic for Alzheimer’s disease and other “tauopathies” and could create MAPT species with toxic properties [11]. The regulation of MAPT expression and epigenetic contributions to it remain to be fully characterized and complex alternative splicing patterns depend on species, tissue and condition [12, 13]. The dynamic internal and external interactions of MAPT are influenced by primary sequence variation, post-translational modifications and polarized charge distribution that determine its site-specific properties responsible for physiological function and neuropathogenic effects [7, 12, 14]. The determination of MAPT functional organization has been hampered by two obstacles. First, only fragments of crystallographic structural information are available for MAPT due to its property as a natively disordered protein [6]. Second, mice lacking MAPT do not have major phenotypic changes indicating that functional redundancies may exist between MAPs. However, genetic data have provided evidence that MAPT is required for the normal development of the human brain since deletions at the locus are associated with severe developmental problems in children [15, 16]. The evolutionary history, key structural motifs and protein properties responsible for functions of the three paralogous vertebrate subfamilies MAPT, MAP2 and MAP4 comprise the main focus of this study. Previous studies have not yet resolved the full species distribution nor duplication order of MAP proteins [2, 17]. The binding of intrinsically disordered proteins to cellular structures and molecular partners is difficult to predict but can influence folding properties and protein turnover [18]; hence there is a need to compile full-length proteins from a broad range of species to obtain a reliable “roadmap” of all potential interaction motifs and domains. Such a comprehensive view overcomes the limitation of studying partial isoforms and highlights all features potentially responsible for the full functionality of MAPT. We have therefore undertaken a molecular evolution study of the MAPT/ MAP2/MAP4 gene superfamily and identified significantly conserved features and patterns of divergence in MAPT that are likely to be (...truncated)