SASDEL5: AICAR-bound human adenylosuccinate lyase (ADSL) (Adenylosuccinate...

Basic information

Entry

Database: SASBDB / ID: SASDEL5

Sample

AICAR-bound human adenylosuccinate lyase (ADSL)

• Adenylosuccinate Lyase (protein), ADSL, Homo sapiens

Function / homology

Function:

AMP biosynthetic process / adenylosuccinate lyase / N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity / (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate lyase (fumarate-forming) activity / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / 'de novo' AMP biosynthetic process / AMP salvage / purine nucleotide biosynthetic process / GMP biosynthetic process / response to muscle activity / 'de novo' IMP biosynthetic process / response to starvation / aerobic respiration / response to nutrient / response to hypoxia / protein-containing complex / identical protein binding / cytosol

Domain/homology:

Adenylosuccinate lyase C-terminus / Adenylosuccinate lyase C-terminal / Adenylosuccinate lyase C-terminus / Adenylosuccinate lyase / Fumarate lyase, conserved site / Fumarate lyases signature. / Fumarate lyase family / Fumarate lyase, N-terminal / Lyase / L-Aspartase-like

Component:

Adenylosuccinate lyase

• Biological species: Homo sapiens (human)
• 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

Sample

• Sample: Name: AICAR-bound human 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); pH: 7.5

Entity #1310

Name: ADSL / Type: protein / Description: Adenylosuccinate Lyase / Formula weight: 55.17 / Num. of mol.: 4 / Source: Homo sapiens / References: UniProt: P30566
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 QVDAYFSPIH 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-bound human 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	0.0751	4.0398

Result

Type of curve: single_conc /

	Experimental	Porod
MW	165 kDa	182 kDa
Volume	-	291 nm3

	Guinier	Guinier error
Forward scattering, I0	153.28	0.06
Radius of gyration, Rg	3.68 nm	-

	Min	Max
Guinier point	1	60