Mucin-type O-glycosylation (O-GalNAcylation) is a structurally diverse post-translational modification (PTM) that serves as a critical molecular interface at the cell surface. Unlike well-characterized PTMs such as phosphorylation or N-glycosylation, the specific roles of O-GalNAcylation in the mammalian brain have long remained poorly understood. Recent studies have begun to reposition this modification as an important regulator of brain architecture and homeostasis. Emerging evidence suggests that it contributes to neuronal organization, neurovascular integrity, synaptic function, and stress-related behavioral phenotypes, and that its dysregulation may be associated with neurological and psychiatric phenotypes. This perspective synthesizes recent advances to highlight the potential importance of a "brain O-glycan code" in brain health and disease. We discuss how remodeling of this glycan landscape may intersect with aging, neuroinflammation, and synaptic plasticity, and propose that glyco-neurobiology provides an additional conceptual layer for understanding brain vulnerability and resilience. Finally, we consider how targeting O-glycosylation pathways may open new avenues for diagnostic and therapeutic strategies in neurodegenerative and psychiatric disease.
Youngsuk Seo, Hyun Joo An, Boyoung Lee· Molecular Psychiatry· 0 citations
Plant receptor kinases perceive diverse peptide signals to coordinate stress responses and developmental programs. The HAESA-LIKE 3 (HSL3/NUT) receptor recognizes CTNIP/SCREW phytocytokines-disulfide-constrained peptides that regulate immune signaling and stress adaptation. However, how HSL3 distinguishes these structurally constrained peptides from linear signaling molecules remains unknown. Here we report near-atomic resolution cryo-EM structures of HSL3 in apo and CTNIP448-70-bound states at ∼2.6 Å, using Arabidopsis CTNIP4 as a representative family member, revealing the mechanism of disulfide-constrained peptide recognition. The conserved CTNIP motif occupies a negatively charged pocket in the C-terminal region of HSL3 through a combination of polar contacts, hydrogen bonds, salt bridges, and van der Waals interactions. The receptor employs a two-step recognition mechanism-electrostatic steering followed by motif anchoring-that enables rapid ligand capture, consistent with the dynamic nature of stress signaling. Notably, an N-glycan at Asn449 directly contacts the CTNIP4 peptide, establishing glycosylation as an active participant in ligand recognition. Structure-guided mutagenesis combined with reactive oxygen species (ROS) burst assays confirmed the functional importance of key binding interfaces. N-terminal truncation experiments revealed a minimal active fragment: CTNIP451-70 supported both rapid ROS production and sustained seedling growth inhibition, whereas the shorter CTNIP454-70 variant retained ROS activity but failed to trigger long-term seedling growth inhibition. Structure-guided coevolutionary analysis across plant lineages reveals patterns of both conserved and variable receptor-ligand interfaces, highlighting evolutionary flexibility while preserving core features of recognition. These conserved recognition principles, mediated by receptor glycosylation and evolutionary plasticity, enable specificity in peptide signaling, with implications for engineering stress-resilient crops.
