Structure and function of the acidic amino acid decarboxylase GADL1

Elaheh Mahootchi, Arne Raasakka,‡ Ingeborg Winge,a,b Weisha Luan,c Petri Kursulaa,c* and Jan Haavika,b,d*

a Department of Biomedicine, University of Bergen, Bergen, Norway, b K. G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, c Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland, and d Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.

‡ These authors made equal contributions

Aims:

Glutamic acid decarboxylase-like protein 1 (GADL1) is a recently discovered pyridoxal 5′-phosphate -dependent enzyme that has been associated with lithium response in bipolar disorder. The expression pattern and activity of GADL1 suggest a role in neurotransmitter and neuroprotectant metabolism, notably in the synthesis of beta-alanine and carnosine in the olfactory bulb. The catalytic properties and crystal structure of mouse GADL1 is described, together with a solution model based on small-angle X-ray scattering data.

Methods:

  • Construct preparation, protein expression and purification
  • Expression and purification of mouse GADL1 (MmGADL1)
  • Crystallization
  • Small-angle X-ray scattering

 

Results:

The substrate specificity and physiological functions of GADL1 are still unclear. While the overall fold and the conformation of the bound PLP are similar to those in other PLP-dependent decarboxylases, GADL1 adopts a more loose conformation in solution, which might have functional relevance in ligand binding and catalysis.

Conclusions:

The structure of MmGADL1 and its flexibility in solution, coupled to structural conservation with other PLP-dependent enzymes, point towards functional relevance of these features within the enzyme family. Future work will concentrate on high-resolution structural details of substrate and inhibitor binding by GADL1, as well as characterization of its metabolic role in mouse tissues.

https://www.ncbi.nlm.nih.gov/pubmed/29372909

 

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