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

Basic information

• Entry: Database: SASBDB / ID: SASDER5

Sample

AICAR/fumarate-bound neanderthal adenylosuccinate lyase (ADSL)

• Adenylosuccinate Lyase (protein), ADSL, Homo sapiens neanderthalensis

• Biological species: Homo sapiens neanderthalensis (Neandertal)
• Citation: Journal: Sci Rep / Year: 2018; Title: Molecular comparison of Neanderthal and Modern Human adenylosuccinate lyase.; Authors: Bart Van Laer / Ulrike Kapp / Montserrat Soler-Lopez / Kaja Moczulska / Svante Pääbo / Gordon Leonard / Christoph Mueller-Dieckmann / ; 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.

Contact author

• Bart Van Laer (ESRF, European Synchrotron Radiation Facility, Grenoble, France)

Models

• Model #2432: ; Type: atomic / Chi-square value: 11.538; Search similar-shape structures of this assembly by Omokage search (details)

Sample

• Sample: Name: AICAR/fumarate-bound neanderthal adenylosuccinate lyase (ADSL); Specimen concentration: 5 mg/ml
• Buffer: Name: 10 mM HEPES, 100 mM NaCl, 1 mM DTT, 1 mM 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), 1mM Fumarate; pH: 7.5

Entity #1311

Name: ADSL / Type: protein / Description: Adenylosuccinate Lyase / Formula weight: 55.142 / Num. of mol.: 4 / Source: Homo sapiens neanderthalensis
Sequence:

GSHMAAGGDH GSPDSYRSPL ASRYASPEMC FVFSDRYKFR TWRQLWLWLA EAEQTLGLPI TDEQIQEMKS NLENIDFKMA AEEEKRLRHD VMAHVHTFGH CCPKAAGIIH LGATSCYVGD NTDLIILRNA LDLLLPKLAR VISRLADFAK ERASLPTLGF THFQPAQLTT VGKRCCLWIQ DLCMDLQNLK RVRDDLRFRG VKGTTGTQAS FLQLFEGDDH KVEQLDKMVT EKAGFKRAFI ITGQTYTRKV DIEVLSVLAS LGASVHKICT DIRLLANLKE MEEPFEKQQI GSSAMPYKRN PMRSERCCSL ARHLMTLVMD PLQTASVQWF ERTLDDSANR RICLAEAFLT ADTILNTLQN ISEGLVVYPK VIERRIRQEL PFMATENIIM AMVKAGGSRQ DCHEKIRVLS QQAASVVKQE GGDNDLIERI QADAYFSPIH SQLDHLLDPS SFTGRASQQV QRFLEEEVYP LLKPYESVMK VKAELCL

Experimental information

• Beam: Instrument name: ESRF BM29 / City: Grenoble / 国: France / Type of source: X-ray synchrotron / Wavelength: 0.099 Å / Dist. spec. to detc.: 2.864 mm
• Detector: Name: Pilatus 1M / Type: Dectris / Pixsize x: 172 mm

Scan

Title: AICAR/fumarate-bound neanderthal adenylosuccinate lyase (ADSL)
Measurement date: Jul 24, 2016 / Storage temperature: 20 °C / Cell temperature: 20 °C / Exposure time: 1 sec. / Number of frames: 10 / Unit: 1/nm /

	Min	Max
Q	0.0467	3.8035

Result

Type of curve: single_conc /

	Experimental	Porod
MW	161 kDa	158 kDa
Volume	-	252 nm3

	Guinier	Guinier error
Forward scattering, I0	152.02	0.07
Radius of gyration, Rg	3.62 nm	0.01

	Min	Max
Guinier point	20	67