MS11-P01 Neanderthal adenylosuccinate lyase: insights in catalysis and link with disease-causing mutation Bart Van Laer (Structural Biology group, European Synchrotron Radiation Facility (ESRF), Grenoble, France) Ulrike Kapp (Structural Biology group, European Synchrotron Radiation Facility (ESRF), Grenoble, France) Montserrat Soler-Lopez (Structural Biology group, European Synchrotron Radiation Facility (ESRF), Grenoble, France) Kaja Moczulska (Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany) Svante Pääbo (Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany) Gordon Leonard (Structural Biology group, European Synchrotron Radiation Facility (ESRF), Grenoble, France) Christoph Mueller-Dieckmann (Structural Biology group, European Synchrotron Radiation Facility (ESRF), Grenoble, France)email: bart.van-laer@esrf.frAdenylosuccinate lyase is a conserved enzyme involved in purine metabolism for which several mutations in the human enzyme (hADSL) are known to affect intelligence and behaviour. During evolution modern humans acquired a specific substitution (Val429Ala) in ADSL distinguishing it from the ancestral variant present in Neanderthals (nADSL). I will present a structural, biophysical and biochemical comparison of hADSL and nADSL aimed at determining whether this substitution is functionally relevant and could be responsible for phenotypical differences between these species. This work shows that hADSL and nADSL differ in thermal stability but not in enzymatic activity. Similar observations are made when comparing native hADSL with hADSL containing the nearby disease-causing Arg426His substitution hinting towards a phenotypical effect. In addition the combined X-ray crystallography and SAXS data reveals that ADSL undergoes conformational changes during catalysis which together with the structure of a hitherto undetermined product bound conformation helps explain the effect of several human disease-causing substitutions.References:

Keywords: Neanderthal, Human disease.