title: Structural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons.
abstract: Mutations in angiogenin (ANG), a member of the ribonuclease A superfamily, are associated with amyotrophic lateral sclerosis (ALS; sporadic and familial) and Parkinson's disease. We have previously shown that ANG is expressed in neurons during neuro-ectodermal differentiation, and that it has both neurotrophic and neuroprotective functions. Here we report the atomic resolution structure of native ANG and 11 ANG-ALS variants. We correlate the structural changes to the effects on neuronal survival and the ability to induce stress granules in neuronal cell lines. ANG-ALS variants that affect the structure of the catalytic site and either decrease or increase the RNase activity affect neuronal survival. Neuronal cell lines expressing the ANG-ALS variants also lack the ability to form stress granules. Our structure-function studies on these ANG-ALS variants are the first to provide insights into the cellular and molecular mechanisms underlying their role in ALS.
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Nethaji
authors.initials: N
authors.lastname: Thiyagarajan
authors.forename: Ross
authors.initials: R
authors.lastname: Ferguson
authors.forename: Vasanta
authors.initials: V
authors.lastname: Subramanian
authors.forename: K Ravi
authors.initials: KR
authors.lastname: Acharya
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003594:Cytoplasmic Granules / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D012259:Ribonuclease, Pancreatic / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C046366:angiogenin; D012259:Ribonuclease, Pancreatic