The evolution of the huntingtin-associated protein 40 (HAP40) in conjunction with huntingtin
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RESEARCH ARTICLE
Open Access
The evolution of the huntingtin‑associated protein 40 (HAP40) in conjunction with huntingtin Manuel Seefelder1, Vikram Alva2, Bin Huang1, Tatjana Engler1, Wolfgang Baumeister3, Qiang Guo3,6, Rubén Fernández‑Busnadiego3,4,5, Andrei N. Lupas2* and Stefan Kochanek1*
Abstract Background: The huntingtin-associated protein 40 (HAP40) abundantly interacts with huntingtin (HTT), the protein that is altered in Huntington’s disease (HD). Therefore, we analysed the evolution of HAP40 and its interaction with HTT. Results: We found that in amniotes HAP40 is encoded by a single-exon gene, whereas in all other organisms it is expressed from multi-exon genes. HAP40 co-occurs with HTT in unikonts, including filastereans such as Capsaspora owczarzaki and the amoebozoan Dictyostelium discoideum, but both proteins are absent from fungi. Outside unikonts, a few species, such as the free-living amoeboflagellate Naegleria gruberi, contain putative HTT and HAP40 orthologs. Biochemically we show that the interaction between HTT and HAP40 extends to fish, and bioinformatic analyses provide evidence for evolutionary conservation of this interaction. The closest homologue of HAP40 in current protein databases is the family of soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAPs). Conclusion: Our results indicate that the transition from a multi-exon to a single-exon gene appears to have taken place by retroposition during the divergence of amphibians and amniotes, followed by the loss of the parental multiexon gene. Furthermore, it appears that the two proteins probably originated at the root of eukaryotes. Conservation of the interaction between HAP40 and HTT and their likely coevolution strongly indicate functional importance of this interaction. Keywords: Huntingtin, Huntingtin-associated protein 40, Soluble N-ethylmaleimide-sensitive factor attachment proteins, Retroposition, Single-exon gene, Molecular evolution, Protein coevolution Background Huntingtin (HTT) is a large intracellular protein with a molecular weight (MW) of 348 kDa, which is functionally involved in diverse cellular processes. These include endocytosis, vesicle transport, autophagy, and *Correspondence: [email protected]; stefan. kochanek@uni‑ulm.de 1 Department of Gene Therapy, Ulm University, 89081 Ulm, Germany 2 Department of Protein Evolution, Max Planck Institute for Developmental Biology, Max‑Planck‑Ring 5, 72076 Tübingen, Germany Full list of author information is available at the end of the article
transcriptional regulation [1]. A mutation in exon 1 of the HTT gene, which results in the pathogenic expansion of a polyglutamine tract near the N-terminus of the protein, causes Huntington’s disease (HD), a lethal neurodegenerative disease with autosomal dominant inheritance [2]. HTT orthologs are present throughout protists and animals, but absent in plants and fungi [3, 4]. In mice, HTT is essential for embryonic development and viability, since HTT nullizygosity results in early embryonic lethality
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