title: The Evolutionarily Conserved Tre2/Bub2/Cdc16 (TBC), Lysin Motif (LysM), Domain Catalytic (TLDc) Domain Is Neuroprotective against Oxidative Stress.
abstract: Oxidative stress is a pathological feature of many neurological disorders; therefore, utilizing proteins that are protective against such cellular insults is a potentially valuable therapeutic approach. Oxidation resistance 1 (OXR1) has been shown previously to be critical for oxidative stress resistance in neuronal cells; deletion of this gene causes neurodegeneration in mice, yet conversely, overexpression of OXR1 is protective in cellular and mouse models of amyotrophic lateral sclerosis. However, the molecular mechanisms involved are unclear. OXR1 contains the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) domain, a motif present in a family of proteins including TBC1 domain family member 24 (TBC1D24), a protein mutated in a range of disorders characterized by seizures, hearing loss, and neurodegeneration. The TLDc domain is highly conserved across species, although the structure-function relationship is unknown. To understand the role of this domain in the stress response, we carried out systematic analysis of all mammalian TLDc domain-containing proteins, investigating their expression and neuroprotective properties in parallel. In addition, we performed a detailed structural and functional study of this domain in which we identified key residues required for its activity. Finally, we present a new mouse insertional mutant of Oxr1, confirming that specific disruption of the TLDc domain in vivo is sufficient to cause neurodegeneration. Our data demonstrate that the integrity of the TLDc domain is essential for conferring neuroprotection, an important step in understanding the functional significance of all TLDc domain-containing proteins in the cellular stress response and disease.
authors.affiliation: From the MRC Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom.
authors.forename: Mattéa J
authors.initials: MJ
authors.lastname: Finelli
authors.affiliation: From the MRC Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom.
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Pulido
authors.affiliation: From the MRC Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom.
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Liu
authors.affiliation: From the MRC Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom.
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
authors.affiliation: From the MRC Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom peter.oliver@dpag.ox.ac.uk.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
mesh_terms: D020816:Amino Acid Motifs; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D019143:Evolution, Molecular; D020690:GTPase-Activating Proteins; D054643:INDEL Mutation; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D017434:Protein Structure, Tertiary
chemical_list: D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; C423572:Oxr1 protein, mouse; C552552:Tbc1d24 protein, mouse
keywords: evolution; mouse; neurobiology; neurodegeneration; neurological disease; neuron; oxidative stress; protein structure