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Structure and function of Semaphorin-5A glycosaminoglycan interactions

Author

Listed:
  • Gergely N. Nagy

    (University of Oxford
    Budapest University of Technology and Economics
    HUN-REN Research Centre for Natural Sciences)

  • Xiao-Feng Zhao

    (University of Michigan Medical School)

  • Richard Karlsson

    (University of Copenhagen)

  • Karen Wang

    (University of Michigan Medical School)

  • Ramona Duman

    (Harwell Science and Innovation Campus)

  • Karl Harlos

    (University of Oxford)

  • Kamel El Omari

    (Harwell Science and Innovation Campus)

  • Armin Wagner

    (Harwell Science and Innovation Campus)

  • Henrik Clausen

    (University of Copenhagen)

  • Rebecca L. Miller

    (University of Copenhagen)

  • Roman J. Giger

    (University of Michigan Medical School
    Department of Neurology)

  • E. Yvonne Jones

    (University of Oxford)

Abstract

Integration of extracellular signals by neurons is pivotal for brain development, plasticity, and repair. Axon guidance relies on receptor-ligand interactions crosstalking with extracellular matrix components. Semaphorin-5A (Sema5A) is a bifunctional guidance cue exerting attractive and inhibitory effects on neuronal growth through the interaction with heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs), respectively. Sema5A harbors seven thrombospondin type-1 repeats (TSR1-7) important for GAG binding, however the underlying molecular basis and functions in vivo remain enigmatic. Here we dissect the structural basis for Sema5A:GAG specificity and demonstrate the functional significance of this interaction in vivo. Using x-ray crystallography, we reveal a dimeric fold variation for TSR4 that accommodates GAG interactions. TSR4 co-crystal structures identify binding residues validated by site-directed mutagenesis. In vitro and cell-based assays uncover specific GAG epitopes necessary for TSR association. We demonstrate that HS-GAG binding is preferred over CS-GAG and mediates Sema5A oligomerization. In vivo, Sema5A:GAG interactions are necessary for Sema5A function and regulate Plexin-A2 dependent dentate progenitor cell migration. Our study rationalizes Sema5A associated developmental and neurological disorders and provides mechanistic insights into how multifaceted guidance functions of a single transmembrane cue are regulated by proteoglycans.

Suggested Citation

  • Gergely N. Nagy & Xiao-Feng Zhao & Richard Karlsson & Karen Wang & Ramona Duman & Karl Harlos & Kamel El Omari & Armin Wagner & Henrik Clausen & Rebecca L. Miller & Roman J. Giger & E. Yvonne Jones, 2024. "Structure and function of Semaphorin-5A glycosaminoglycan interactions," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46725-7
    DOI: 10.1038/s41467-024-46725-7
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    References listed on IDEAS

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