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TitleMolecular comparison of Neanderthal and Modern Human adenylosuccinate lyase.
Journal, issue, pagesSci Rep, Vol. 8, Issue 1, Page 18008, Year 2018
Publish dateDec 20, 2018
AuthorsBart Van Laer / Ulrike Kapp / Montserrat Soler-Lopez / Kaja Moczulska / Svante Pääbo / Gordon Leonard / Christoph Mueller-Dieckmann /
PubMed AbstractThe 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. ...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.
External linksSci Rep / PubMed:30573755 / PubMed Central
MethodsSAS (X-ray synchrotron) / X-ray diffraction
Resolution1.7 - 2.4 Å
Structure data

SASDEG5: apo human adenylosuccinate lyase (ADSL) (Adenylosuccinate Lyase, ADSL)
Method: SAXS/SANS

SASDEH5: AMP/fumarate-bound human adenylosuccinate lyase (ADSL)
Method: SAXS/SANS

SASDEJ5: AICAR/fumarate-bound human adenylosuccinate lyase (ADSL)
Method: SAXS/SANS

SASDEK5: AMP-bound human adenylosuccinate lyase (ADSL) (Adenylosuccinate Lyase, ADSL)
Method: SAXS/SANS

SASDEL5: AICAR-bound human adenylosuccinate lyase (ADSL) (Adenylosuccinate Lyase, ADSL)
Method: SAXS/SANS

SASDEM5:
apo neanderthal adenylosuccinate lyase (ADSL) (Adenylosuccinate Lyase, ADSL)
Method: SAXS/SANS

SASDEN5:
AMP/fumarate-bound neanderthal adenylosuccinate lyase (ADSL)
Method: SAXS/SANS

SASDEP5: AMP-bound neanderthal adenylosuccinate lyase (ADSL)
Method: SAXS/SANS

SASDEQ5: AICAR-bound neanderthal adenylosuccinate lyase (ADSL)
Method: SAXS/SANS

SASDER5:
AICAR/fumarate-bound neanderthal adenylosuccinate lyase (ADSL)
Method: SAXS/SANS

PDB-5nx8:
Crystal structure of Neanderthal Adenylosuccinate Lyase (ADSL)
Method: X-RAY DIFFRACTION / Resolution: 1.7 Å

PDB-5nx9:
Crystal structure of Neanderthal Adenylosuccinate Lyase (ADSL) in complex with its products AMP and fumarate
Method: X-RAY DIFFRACTION / Resolution: 2.3 Å

PDB-5nxa:
Crystal structure of Neanderthal Adenylosuccinate Lyase (ADSL)in complex with its products AICAR and fumarate
Method: X-RAY DIFFRACTION / Resolution: 2.4 Å

Chemicals

ChemComp-PEG:
DI(HYDROXYETHYL)ETHER / Diethylene glycol

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-CL:
Unknown entry / Chloride

ChemComp-HOH:
WATER / Water

ChemComp-AMP:
ADENOSINE MONOPHOSPHATE / AMP*YM / Adenosine monophosphate

ChemComp-FUM:
FUMARIC ACID / Fumaric acid

ChemComp-2SA:
2-[9-(3,4-DIHYDROXY-5-PHOSPHONOOXYMETHYL-TETRAHYDRO-FURAN-2-YL)-9H-PURIN-6-YLAMINO]-SUCCINIC ACID

ChemComp-SSS:
N-{[5-AMINO-1-(5-O-PHOSPHONO-BETA-D-ARABINOFURANOSYL)-1H-IMIDAZOL-4-YL]CARBONYL}-L-ASPARTIC ACID

ChemComp-AMZ:
AMINOIMIDAZOLE 4-CARBOXAMIDE RIBONUCLEOTIDE / AICA ribonucleotide

Source
  • Homo sapiens (human)
  • homo sapiens neanderthalensis (Neandertal)
KeywordsLYASE / Adenylosuccinate Lyase / fumarase

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