title: Kelch Domain of Gigaxonin Interacts with Intermediate Filament Proteins Affected in Giant Axonal Neuropathy.
abstract: Patients with giant axonal neuropathy (GAN) show progressive loss of motor and sensory function starting in childhood and typically live for less than 30 years. GAN is caused by autosomal recessive mutations leading to low levels of gigaxonin (GIG), a ubiquitously-expressed BTB/Kelch cytoplasmic protein believed to be an E3 ligase substrate adaptor. GAN pathology is characterized by aggregates of intermediate filaments (IFs) in multiple tissues. To delineate the molecular pathway between GIG deficiency and IF pathology, we undertook a proteomic screen to identify the normal binding partners of GIG. Prominent among them were several classes of IFs, including the neurofilament subunits whose accumulation leads to the axonal swellings for which GAN is named. We showed these interactions were dependent on the Kelch domain of GIG. Furthermore, we identified the E3 ligase MYCBP2 and the heat shock proteins HSP90AA1/AB1 as interactors with the BTB domain that may result in the ubiquitination and subsequent degradation of intermediate filaments. Our open-ended proteomic screen provides support to GIG's role as an adaptor protein, linking IF proteins through its Kelch domain to the ubiquitin pathway proteins via its BTB domain, and points to future approaches for reversing the phenotype in human patients.
authors.affiliation: Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, New York, United States of America; Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, New York, United States of America; Departments of Pathology and Cell Biology, Neurology, and Neuroscience, Columbia University Medical Center, New York, New York, United States of America; Columbia Stem Cell Initiative, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Johnson-Kerner
authors.affiliation: Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, New York, United States of America; Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Garcia Diaz
authors.affiliation: Collaborations in Chemistry, Fuquay-Varina, North Carolina, United States of America.
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.affiliation: Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, New York, United States of America; Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, New York, United States of America; Departments of Pathology and Cell Biology, Neurology, and Neuroscience, Columbia University Medical Center, New York, New York, United States of America; Columbia Stem Cell Initiative, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Hynek
authors.initials: H
authors.lastname: Wichterle
mesh_terms: D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000378:metabolism*; D056768:Giant Axonal Neuropathy / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D011485:Protein Binding; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D040901:Proteomics; D013329:Structure-Activity Relationship
chemical_list: D003598:Cytoskeletal Proteins; C416508:GAN protein, human; D007381:Intermediate Filament Proteins