ERAB (1) is believed to be involved in Alzheimer’s disease, where it is supposed to interact with the amyloid b-peptide. The amyloid b-peptide forms fibrils in neuronal tissue, which cause cell death. It has also been shown that ERAB have catalytic activity versus L-3-Hydroxy-acyl-CoA and the protein is a member of the Short-chain Dehydrogenases/Reductases (SDR) family (2). SDR is a divergent family of NAD(P)H dependent dehydrogenases or reductases that participates in many metabolic pathways. The members of the family are distantly homologous but have a conserved three dimensional structure, which makes homology modelling of ERAB possible.
The model is created to search for clues to how the amyloid b-peptide and ERAB might interact. Since the NMR structure of the amyloid b-peptide was determined and published earlier this year, we hope that we can use our model to get more information about possible interactions between ERAB and the amyloid b-peptide. ERAB is a homotetrameric protein with subunits of 261 amino acid residues. Secondary structure prediction implies that ERAB follows the same overall fold as 20-b-hydroxysteroid dehydrogenase (20b-HSD) (PDB code 2hsd) (3) and 7-alpha hydroxysteroid dehydrogenase (PDB code 1fmc). The closer sequence relationship between ERAB and 20b HSD made us use the 20b HSD as the template for the homology modelling. ICM (4) was used for the homology modelling of one subunit. The placement of the NAD+ was taken directly from the pdb-file.
The model has the general SDR fold with a central seven-stranded b-sheet surrounded by helices arranged in b-a-b folds. The catalytic tyrosine (position 168) is located in a cleft that is covered by the substrate-binding loop (207-221) similarly to the experimentally determined structures of the SDR family.
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The image to the right is the predicted structure of ERAB (red) superimposed on the structure of 20-beta hydroxysteroid dehydrogenase (cyan). The image shows that ERAB follows the general SDR fold. |