title: Amino acid sequence and structural comparison of BACE1 and BACE2 using evolutionary trace method.
abstract: Beta-amyloid precursor protein cleavage enzyme 1 (BACE1) and beta-amyloid precursor protein cleavage enzyme 2 (BACE2), members of aspartyl protease family, are close homologues and have high similarity in their protein crystal structures. However, their enzymatic properties differ leading to disparate clinical consequences. In order to identify the residues that are responsible for such differences, we used evolutionary trace (ET) method to compare the amino acid conservation patterns of BACE1 and BACE2 in several mammalian species. We found that, in BACE1 and BACE2 structures, most of the ligand binding sites are conserved which indicate their enzymatic property of aspartyl protease family members. The other conserved residues are more or less randomly localized in other parts of the structures. Four group-specific residues were identified at the ligand binding site of BACE1 and BACE2. We postulated that these residues would be essential for selectivity of BACE1 and BACE2 biological functions and could be sites of interest for the design of selective inhibitors targeting either BACE1 or BACE2.
authors.affiliation: Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Hoda
authors.identifier: 0000-0001-9490-6441
authors.initials: H
authors.lastname: Mirsafian
authors.affiliation: Allergy and Immunology Research Centre, Institute for Medical Research, Jalan Pahang, 50588 Kuala Lumpur, Malaysia.
authors.forename: Adiratna
authors.initials: A
authors.lastname: Mat Ripen
authors.affiliation: Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia ; Centre of Research for Computational Sciences and Informatics in Biology, Bioindustry, Environment, Agriculture and Healthcare (CRYSTAL), University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Amir Feisal
authors.initials: AF
authors.lastname: Merican
authors.affiliation: Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia ; Centre of Research for Computational Sciences and Informatics in Biology, Bioindustry, Environment, Agriculture and Healthcare (CRYSTAL), University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Saharuddin
authors.initials: S
authors.lastname: Bin Mohamad
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: D000596:Amino Acids; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human