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  Molecular comparison of Neanderthal and Modern Human adenylosuccinate lyase

Van Laer, B., Kapp, U., Soler-Lopez, M., Moczulska, K., Pääbo, S., Leonard, G., et al. (2018). Molecular comparison of Neanderthal and Modern Human adenylosuccinate lyase. Scientific Reports, 8: 18008. doi:10.1038/s41598-018-36195-5.

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Laer_Molecular_SciRep_2018.pdf (Publisher version), 4MB
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This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Van Laer, Bart, Author
Kapp, Ulrike, Author
Soler-Lopez, Montserrat, Author
Moczulska, Kaja1, Author           
Pääbo, Svante1, Author                 
Leonard, Gordon, Author
Mueller-Dieckmann, Christoph, Author
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1Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Max Planck Society, ou_1497672              

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 Abstract: The availability of genomic data from extinct homini such as Neanderthals has caused a revolution in palaeontology allowing the identification of modern human-specific protein substitutions. Currently, little is known as to how these substitutions alter the proteins on a molecular level. Here, we investigate adenylosuccinate lyase, a conserved enzyme involved in purine metabolism for which several substitutions in the modern human protein (hADSL) have been described to affect intelligence and behaviour. During evolution, modern humans acquired a specific substitution (Ala429Val) in ADSL distinguishing it from the ancestral variant present in Neanderthals (nADSL). We show here that despite this conservative substitution being solvent exposed and located distant from the active site, there is a difference in thermal stability, but not enzymology or ligand binding between nADSL and hADSL. Substitutions near residue 429 which do not profoundly affect enzymology were previously reported to cause neurological symptoms in humans. This study also reveals that ADSL undergoes conformational changes during catalysis which, together with the crystal structure of a hitherto undetermined product bound conformation, explains the molecular origin of disease for several modern human ADSL mutants.

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Language(s): eng - English
 Dates: 2018-12-202018
 Publication Status: Issued
 Pages: 14
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41598-018-36195-5
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Title: Scientific Reports
Source Genre: Journal
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Pages: - Volume / Issue: 8 Sequence Number: 18008 Start / End Page: - Identifier: ISSN: 2045-2322