Huntingtin-associated protein 1: Eutherian adaptation from a TRAK-like protein, conserved gene promoter elements, and localization in the human intestine

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dc.contributor.author Lumsden, Amanda L
dc.contributor.author Young, Richard L
dc.contributor.author Pezos, Nektaria
dc.contributor.author Keating, Damien John
dc.date.accessioned 2016-12-05T05:18:01Z
dc.date.available 2016-12-05T05:18:01Z
dc.date.issued 2016-10-13
dc.description 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. en
dc.description.abstract Background: Huntingtin-associated Protein 1 (HAP1) is expressed in neurons and endocrine cells, and is critical for postnatal survival in mice. HAP1 shares a conserved “HAP1_N” domain with TRAfficking Kinesin proteins TRAK1 and TRAK2 (vertebrate), Milton (Drosophila) and T27A3.1 (C. elegans). HAP1, TRAK1 and TRAK2 have a degree of common function, particularly regarding intracellular receptor trafficking. However, TRAK1, TRAK2 and Milton (which have a “Milt/TRAK” domain that is absent in human and rodent HAP1) differ in function to HAP1 in that they are mitochondrial transport proteins, while HAP1 has emerging roles in starvation response. We have investigated HAP1 function by examining its evolution, and upstream gene promoter sequences. We performed phylogenetic analyses of the HAP1_N domain family of proteins, incorporating HAP1 orthologues (identified by genomic synteny) from 5 vertebrate classes, and also searched the Dictyostelium proteome for a common ancestor. Computational analyses of mammalian HAP1 gene promoters were performed to identify phylogenetically conserved regulatory motifs. Results: We found that as recently as marsupials, HAP1 contained a Milt/TRAK domain and was more similar to TRAK1 and TRAK2 than to eutherian HAP1. The Milt/TRAK domain likely arose post multicellularity, as it was absent in the Dictyostelium proteome. It was lost from HAP1 in the eutherian lineage, and also from T27A3.1 in C. elegans. The HAP1 promoter from human, mouse, rat, rabbit, horse, dog, Tasmanian devil and opossum contained common sites for transcription factors involved in cell cycle, growth, differentiation, and stress response. A conserved arrangement of regulatory elements was identified, including sites for caudal-related homeobox transcription factors (CDX1 and CDX2), and myc-associated factor X (MAX) in the region of the TATA box. CDX1 and CDX2 are intestine-enriched factors, prompting investigation of HAP1 protein expression in the human duodenum. HAP1 was localized to singly dispersed mucosal cells, including a subset of serotonin-positive enterochromaffin cells. Conclusion: We have identified eutherian HAP1 as an evolutionarily recent adaptation of a vertebrate TRAK protein-like ancestor, and found conserved CDX1/CDX2 and MAX transcription factor binding sites near the TATA box in mammalian HAP1 gene promoters. We also demonstrated that HAP1 is expressed in endocrine cells of the human gut. en
dc.identifier.citation Lumsden, A. L., Keating, D. J., Young, R., & Pezos, N. (2016). Huntingtin-associated protein 1: Eutherian adaptation from a TRAK-like protein, conserved gene promoter elements, and localization in the human intestine. BMC Evolutionary Biology, 16(1) en
dc.identifier.doi https://doi.org/10.1186/s12862-016-0780-3 en
dc.identifier.issn 1471-2148
dc.identifier.uri http://hdl.handle.net/2328/36818
dc.language.iso en
dc.oaire.license.condition.license CC-BY
dc.publisher BioMed Central en
dc.rights © 2016 The Author(s). Open Access en
dc.rights.holder The Author(s). en
dc.subject HAP1 en
dc.subject TRAK1 en
dc.subject TRAK2 en
dc.subject Milton en
dc.subject CDX1 en
dc.subject CDX2 en
dc.subject TATA-binding protein en
dc.subject Myc-associated factor X, en
dc.subject Serotonin en
dc.subject Enterochromaffin en
dc.title Huntingtin-associated protein 1: Eutherian adaptation from a TRAK-like protein, conserved gene promoter elements, and localization in the human intestine en
dc.type Article en
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