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Front Genet
2013 Dec 17;4:293. doi: 10.3389/fgene.2013.00293.
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A tale of two drug targets: the evolutionary history of BACE1 and BACE2.
Southan C
,
Hancock JM
.
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The beta amyloid (APP) cleaving enzyme (BACE1) has been a drug target for Alzheimer's Disease (AD) since 1999 with lead inhibitors now entering clinical trials. In 2011, the paralog, BACE2, became a new target for type II diabetes (T2DM) having been identified as a TMEM27 secretase regulating pancreatic β cell function. However, the normal roles of both enzymes are unclear. This study outlines their evolutionary history and new opportunities for functional genomics. We identified 30 homologs (UrBACEs) in basal phyla including Placozoans, Cnidarians, Choanoflagellates, Porifera, Echinoderms, Annelids, Mollusks and Ascidians (but not Ecdysozoans). UrBACEs are predominantly single copy, show 35-45% protein sequence identity with mammalian BACE1, are ~100 residues longer than cathepsin paralogs with an aspartyl protease domain flanked by a signal peptide and a C-terminal transmembrane domain. While multiple paralogs in Trichoplax and Monosiga pre-date the nervous system, duplication of the UrBACE in fish gave rise to BACE1 and BACE2 in the vertebrate lineage. The latter evolved more rapidly as the former maintained the emergent neuronal role. In mammals, Ka/Ks for BACE2 is higher than BACE1 but low ratios for both suggest purifying selection. The 5' exons show higher Ka/Ks than the catalytic section. Model organism genomes show the absence of certain BACE human substrates when the UrBACE is present. Experiments could thus reveal undiscovered substrates and roles. The human protease double-target status means that evolutionary trajectories and functional shifts associated with different substrates will have implications for the development of clinical candidates for both AD and T2DM. A rational basis for inhibition specificity ratios and assessing target-related side effects will be facilitated by a more complete picture of BACE1 and BACE2 functions informed by their evolutionary context.
Figure 1. InterProScan Sequence Features. Representative examples are shown for two Ur-BACEs (A)
Monosiga ovata A (Mono_ovat_A), (B)
Strongylocentrotus purpuratus (Stron_purp), (C) human BACE1 (Hum_BACE1) (D) human BACE2 (Hum_BACE2), and (E) a cathepsin from Monosiga ovata (Mono_ovat_cath01). The protein length is indicated.
Figure 2. Summary of InterProScan pattern hits for the proteins included in Table 2.
Figure 3. Protein trees of BACE protein sequences. Sequences are labeled as in Table 2. Black dots indicate sequences with accession numbers for complete ORFs in Table 2. Solid vertical bars represent bootstrap values of 100% and open bars represent bootstrap values of 95% or greater but less than 100%. Sequences corresponding to high order taxa are enclosed in colored boxes as indicated by the legends in the figures. (A): All sequences analyzed; (B): Ur-BACE sequences only.
Figure 4. Blocks generated from the UrBACE sequences. The six conserved regions are shown in N-terminal to C-terminal order.
Figure 5. Sequence Logos for the six conserved UrBACE blocks in N-terminal to C-terminal order (with spacing shown in Table 2). Residue letter height is an index of conservation.
Figure 6. The blocks from Figure 3 and Logos from Figure 4, aligned against a BACE1 PDBSum entry. Among the many entries with different ligands the longest sequence was chosen, 3lpi. The 2D display is shaded red to purple for conserved residues but note these are derived from BACE1 alignments (i.e., do not include UrBACEs). The secondary structure elements in dark blue and other marked features are described in the PDBSum features. The red arrows, added from this work, correspond to the six UrBACE sequence blocks.
Figure 7. T-Coffee alignments of C-termini for (A) BACE1, (B) BACE2, and (C) UrBACE. The inputs were restricted to complete termini but also needed the removal of the Monosiga and Trichoplax sequences to give an informative result for panel (C).
Figure 8. Presence/absence of BACE1 and BACE substrates on six selected proteome sets from completed genomes. Boxes to the right represent likely orthology matches to the human sequences for BACE1 (P56817), APP (P05067), NRG1 (Q02297), SCN2B (O60939), TMEM27 (Q9HBJ8), and PSEN1 (P49768). An X represents their probable absence by low BLASTP score.
Acquati,
The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region.
2000, Pubmed
Acquati,
The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region.
2000,
Pubmed
Anwar,
Improved data retrieval from TreeBASE via taxonomic and linguistic data enrichment.
2009,
Pubmed
Arntfield,
β-Cell evolution: How the pancreas borrowed from the brain: The shared toolbox of genes expressed by neural and pancreatic endocrine cells may reflect their evolutionary relationship.
2011,
Pubmed
Attwood,
The PRINTS database: a fine-grained protein sequence annotation and analysis resource--its status in 2012.
2012,
Pubmed
Burkhardt,
Primordial neurosecretory apparatus identified in the choanoflagellate Monosiga brevicollis.
2011,
Pubmed
Carmine-Simmen,
Neurotoxic effects induced by the Drosophila amyloid-beta peptide suggest a conserved toxic function.
2009,
Pubmed
Crooks,
WebLogo: a sequence logo generator.
2004,
Pubmed
Dahlberg,
Refining the Ciona intestinalis model of central nervous system regeneration.
2009,
Pubmed
Dislich,
The Membrane-Bound Aspartyl Protease BACE1: Molecular and Functional Properties in Alzheimer's Disease and Beyond.
2012,
Pubmed
Dominguez,
Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice.
2005,
Pubmed
Drew,
Data deposition: Missing data mean holes in tree of life.
2013,
Pubmed
Durham,
Progress toward the discovery and development of efficacious BACE inhibitors.
2006,
Pubmed
Esterházy,
Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass.
2011,
Pubmed
Farzan,
BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.
2000,
Pubmed
Fleck,
BACE1 dependent neuregulin processing: review.
2012,
Pubmed
Gascuel,
BIONJ: an improved version of the NJ algorithm based on a simple model of sequence data.
1997,
Pubmed
Goedert,
A century of Alzheimer's disease.
2006,
Pubmed
Gonnet,
Surprising results on phylogenetic tree building methods based on molecular sequences.
2012,
Pubmed
Hedges,
TimeTree: a public knowledge-base of divergence times among organisms.
2006,
Pubmed
Hemming,
Identification of beta-secretase (BACE1) substrates using quantitative proteomics.
2009,
Pubmed
Henikoff,
Automated construction and graphical presentation of protein blocks from unaligned sequences.
1995,
Pubmed
Hilpert,
β-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease.
2013,
Pubmed
Hogl,
Determination of the proteolytic cleavage sites of the amyloid precursor-like protein 2 by the proteases ADAM10, BACE1 and γ-secretase.
2011,
Pubmed
Hogl,
Label-free quantitative analysis of the membrane proteome of Bace1 protease knock-out zebrafish brains.
2013,
Pubmed
Holland,
Gene duplications and the origins of vertebrate development.
1994,
Pubmed
Hufton,
Early vertebrate whole genome duplications were predated by a period of intense genome rearrangement.
2008,
Pubmed
Hussain,
Identification of a novel aspartic protease (Asp 2) as beta-secretase.
1999,
Pubmed
Hussain,
ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site.
2000,
Pubmed
Jonsson,
A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.
2012,
Pubmed
Karran,
The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics.
2011,
Pubmed
King,
The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans.
2008,
Pubmed
Kosakovsky Pond,
Not so different after all: a comparison of methods for detecting amino acid sites under selection.
2005,
Pubmed
Kovacs,
Alzheimer's secretases regulate voltage-gated sodium channels.
2010,
Pubmed
Kuhn,
Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons.
2012,
Pubmed
Kuraku,
Timing of genome duplications relative to the origin of the vertebrates: did cyclostomes diverge before or after?
2009,
Pubmed
Lal,
Regulated intramembrane proteolysis: signaling pathways and biological functions.
2011,
Pubmed
Laskowski,
PDBsum new things.
2009,
Pubmed
Leebens-Mack,
Taking the first steps towards a standard for reporting on phylogenies: Minimum Information About a Phylogenetic Analysis (MIAPA).
2006,
Pubmed
Lichtenthaler,
Regulated intramembrane proteolysis--lessons from amyloid precursor protein processing.
2011,
Pubmed
Liebeskind,
Evolution of sodium channels predates the origin of nervous systems in animals.
2011,
Pubmed
Lynch,
The evolutionary fate and consequences of duplicate genes.
2000,
Pubmed
Lynch,
The probability of duplicate gene preservation by subfunctionalization.
2000,
Pubmed
Lynch,
The probability of preservation of a newly arisen gene duplicate.
2001,
Pubmed
Löytynoja,
webPRANK: a phylogeny-aware multiple sequence aligner with interactive alignment browser.
2010,
Pubmed
Ma,
Involvement of beta-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity.
2007,
Pubmed
May,
Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor.
2011,
Pubmed
Miyata,
Divergence pattern of animal gene families and relationship with the Cambrian explosion.
2001,
Pubmed
Morin,
Sequencing and analysis of 10,967 full-length cDNA clones from Xenopus laevis and Xenopus tropicalis reveals post-tetraploidization transcriptome remodeling.
2006,
Pubmed
Olson,
Recent progress in the medicinal chemistry of gamma-secretase inhibitors.
2008,
Pubmed
Osigus,
Chasing the urmetazoon: striking a blow for quality data?
2013,
Pubmed
Papadopoulos,
COBALT: constraint-based alignment tool for multiple protein sequences.
2007,
Pubmed
Pieler,
Forgotten and novel aspects in pancreas development.
2006,
Pubmed
Probst,
Small-molecule BACE1 inhibitors: a patent literature review (2006 - 2011).
2012,
Pubmed
Pruitt,
The consensus coding sequence (CCDS) project: Identifying a common protein-coding gene set for the human and mouse genomes.
2009,
Pubmed
Quigley,
Pigment pattern evolution by differential deployment of neural crest and post-embryonic melanophore lineages in Danio fishes.
2004,
Pubmed
Rausch,
Segment-based multiple sequence alignment.
2008,
Pubmed
Rawlings,
Pepsin homologues in bacteria.
2009,
Pubmed
Rawlings,
MEROPS: the peptidase database.
2008,
Pubmed
Rochin,
BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells.
2013,
Pubmed
Ruan,
TreeFam: 2008 Update.
2008,
Pubmed
Schechter,
Cathepsins S, B and L with aminopeptidases display β-secretase activity associated with the pathogenesis of Alzheimer's disease.
2011,
Pubmed
Selkoe,
Presenilin: running with scissors in the membrane.
2007,
Pubmed
Shaffer,
The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage.
2013,
Pubmed
Singh,
FigShare.
2011,
Pubmed
Sinha,
Purification and cloning of amyloid precursor protein beta-secretase from human brain.
1999,
Pubmed
Southan,
Exploiting new genome data and Internet resources for the phylogenetic analysis of proteases, substrates and inhibitors.
2007,
Pubmed
Southan,
BACE2 as a new diabetes target: a patent review (2010 - 2012).
2013,
Pubmed
Southan,
Analysis of in vitro bioactivity data extracted from drug discovery literature and patents: Ranking 1654 human protein targets by assayed compounds and molecular scaffolds.
2011,
Pubmed
Srivastava,
The Trichoplax genome and the nature of placozoans.
2008,
Pubmed
Stamford,
Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aβ Reduction.
2012,
Pubmed
Stockley,
Understanding BACE1: essential protease for amyloid-beta production in Alzheimer's disease.
2008,
Pubmed
Stoltzfus,
Sharing and re-use of phylogenetic trees (and associated data) to facilitate synthesis.
2012,
Pubmed
Stützer,
Systematic proteomic analysis identifies β-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic β-cells.
2013,
Pubmed
Sun,
BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome.
2006,
Pubmed
Sun,
Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes.
2005,
Pubmed
Toyn,
Viable mouse gene ablations that robustly alter brain Aβ levels are rare.
2010,
Pubmed
Vassar,
Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.
1999,
Pubmed
Venkatesh,
Survey sequencing and comparative analysis of the elephant shark (Callorhinchus milii) genome.
2007,
Pubmed
Venugopal,
Beta-secretase: structure, function, and evolution.
2008,
Pubmed
Vetrivel,
Alzheimer disease Abeta production in the absence of S-palmitoylation-dependent targeting of BACE1 to lipid rafts.
2009,
Pubmed
Weiss,
Design and preparation of a potent series of hydroxyethylamine containing β-secretase inhibitors that demonstrate robust reduction of central β-amyloid.
2012,
Pubmed
Xia,
γ-Secretase modulator in Alzheimer's disease: shifting the end.
2012,
Pubmed
Yan,
Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity.
1999,
Pubmed
Zakon,
Adaptive evolution of voltage-gated sodium channels: the first 800 million years.
2012,
Pubmed
auf dem Keller,
Protease research in the era of systems biology.
2007,
Pubmed
van Bebber,
Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes.
2013,
Pubmed