title: Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules.
abstract: Septin 9 (SEPT9) interacts with microtubules (MTs) and is mutated in hereditary neuralgic amyotrophy (HNA), an autosomal-dominant neuropathy. The mechanism of SEPT9 interaction with MTs and the molecular basis of HNA are unknown. Here, we show that the N-terminal domain of SEPT9 contains the novel repeat motifs K/R-x-x-E/D and R/K-R-x-E, which bind and bundle MTs by interacting with the acidic C-terminal tails of β-tubulin. Alanine scanning mutagenesis revealed that the K/R-R/x-x-E/D motifs pair electrostatically with one another and the tails of β-tubulin, enabling septin–septin interactions that link MTs together. SEPT9 isoforms lacking repeat motifs or containing the HNA-linked mutation R88W, which maps to the R/K-R-x-E motif, diminished intracellular MT bundling and impaired asymmetric neurite growth in PC-12 cells. Thus, the SEPT9 repeat motifs bind and bundle MTs, and thereby promote asymmetric neurite growth. These results provide the first insight into the mechanism of septin interaction with MTs and the molecular and cellular basis of HNA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Bai
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Bowen
authors.forename: Tara K
authors.initials: TK
authors.lastname: Knox
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Zhou
authors.forename: Manuela
authors.initials: M
authors.lastname: Pendziwiat
authors.forename: Gregor
authors.initials: G
authors.lastname: Kuhlenbäumer
authors.forename: Charles V
authors.initials: CV
authors.lastname: Sindelar
authors.forename: Elias T
authors.initials: ET
authors.lastname: Spiliotis
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D020968:Brachial Plexus Neuritis / Q000235:genetics*; D004285:Dogs; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008870:Microtubules / Q000378:metabolism*; D016716:PC12 Cells; D020033:Protein Isoforms; D051381:Rats; D058112:Septins / Q000737:chemistry*; D014404:Tubulin / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D014404:Tubulin; C474315:SEPTIN9 protein, human; D058112:Septins