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Summary Katanin was the first microtubule (MT)-severing enzyme discovered, but how katanin executes MT severing remains poorly understood. Here, we report X-ray crystal structures of the apo and ATPγS-bound states of the catalytic AAA domain of human katanin p60 at 3.0 and 2.9 Å resolution, respectively. Comparison of the two structures reveals conformational changes induced by ATP binding and how such changes ensure hexamer stability. Moreover, we uncover structural details of pore loops (PLs) and show that Arg283, a residue unique to katanin among MT-severing enzymes, protrudes from PL1 and lines the entry of the catalytic pore. Functional studies suggest that PL1 and Arg283 play essential roles in the recognition and remodeling of the glutamylated, C-terminal tubulin tail and regulation of axon growth. In addition, domain-swapping experiments in katanin and spastin suggest that the non-homologous N-terminal region, which contains the MT-interacting and trafficking domain and a linker, confers specificity to the severing process. Graphical Abstract Highlights • Structures of the apo and ATPγS-bound AAA domain of katanin p60 are determined • The YRG motif of pore loop 1, unique to katanin, is crucial for katanin activity • Katanin remodels glutamylated microtubules and controls axon growth • Katanin and spastin recognize and remodel microtubules in distinct ways Shin et al. report structures of the apo and ATPγS-bound AAA domain of katanin p60. Structural modeling and functional studies suggest that Arg283 in the YRG motif, unique to katanin, crowns the entry of the catalytic core and is essential for remodeling of glutamylated microtubules and regulation of axon growth. [ABSTRACT FROM AUTHOR]

The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (WNT)/ planar cell polarity (PCP) signaling pathway and BRAF protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRAF) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRAF inhibitor, vemurafenib, significantly extends the survival of PDX models. This study provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance, highlighting promising therapeutic strategies for clinical intervention. [Display omitted] • Longitudinal proteogenomic analysis reveals increased neuronal state at recurrence • Neuronal transition associates with activation of WNT/PCP pathway and BRAF kinase • Resistance to therapy via neuronal transition is recapitulated in GBM PDX models • BRAF kinase inhibition impairs the neuronal transition of GBM at recurrence Kim et al. reveal that glioblastoma develops therapeutic resistance through a neuronal transition caused by changes in the WNT/PCP pathway and BRAF kinase, as shown by extensive proteogenomic analysis. Notably, inhibiting BRAF kinase disrupts this lethal transformation, offering potential therapeutic avenues. [ABSTRACT FROM AUTHOR]

Highlights • Retrieval of contextual fear memory increases the membrane excitability. • Propranolol or NMDAR and PKA inhibition diminishes membrane hyperexcitability. • β-adrenergic signaling is required for the destabilization of contextual fear memory. Abstract Memory reconsolidation is the process by which previously consolidated memories reenter a labile state through reactivation of the memory trace and are actively consolidated through de novo protein synthesis. Although extensive studies have shown that β-adrenergic signaling plays a critical role in the restabilization of reactivated memory, its role in the destabilization of long-term memory is not well-studied. In this study, we found that membrane excitability increased in hippocampal CA1 neurons immediately after the retrieval of contextual fear memory. Interestingly, this increase in membrane excitability diminished after treatment with propranolol (a β-adrenergic receptor antagonist), an NMDA receptor antagonist, and a PKA inhibitor. In addition, we found that administration of propranolol prior to, but not after, the retrieval of fear memory ameliorated the memory impairment caused by anisomycin, indicating that inhibition of β-adrenergic signaling blocks the destabilization of contextual fear memory. Taken together, these results indicate that β-adrenergic signaling via NMDA receptors and PKA signaling pathway induces a labile state of long-term memory through increased neuronal membrane excitability. [ABSTRACT FROM AUTHOR]