Structure and function of Semaphorin-5A glycosaminoglycan interactions
Gergely N Nagy1,2,3, Xiao-Feng Zhao4, Richard Karlsson5
1Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. nagy.gergely.nandor@vbk.bme.hu.
Nature Communications
|March 29, 2024
Summary
Semaphorin-5A (Sema5A) interacts with heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs) to guide neuronal growth. This study reveals the structural basis for these interactions, crucial for brain development and repair.
Area of Science:
- Neuroscience
- Molecular Biology
- Structural Biology
Background:
- Neuronal development, plasticity, and repair depend on integrating extracellular signals.
- Axon guidance involves receptor-ligand interactions with the extracellular matrix.
- Semaphorin-5A (Sema5A) is a bifunctional guidance cue interacting with heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs).
Purpose of the Study:
- To elucidate the structural basis for Semaphorin-5A (Sema5A) binding specificity to glycosaminoglycans (GAGs).
- To investigate the in vivo functional significance of Sema5A:GAG interactions in neuronal development.
Main Methods:
- X-ray crystallography to determine the structure of Sema5A thrombospondin repeats (TSRs) bound to GAGs.
- Site-directed mutagenesis to validate GAG-binding residues.
- In vitro and cell-based assays to assess GAG binding and Sema5A oligomerization.
- In vivo studies in model organisms to evaluate the role of Sema5A:GAG interactions in neuronal migration.
Main Results:
- Revealed a dimeric fold variation in TSR4 accommodating GAG binding, identifying key residues.
- Demonstrated preferential binding of Sema5A to HS-GAG over CS-GAG, mediating Sema5A oligomerization.
- Established that Sema5A:GAG interactions are essential for Sema5A function in vivo, regulating Plexin-A2 dependent dentate progenitor cell migration.
Conclusions:
- Sema5A binding to specific GAGs, particularly HS-GAG, is structurally and functionally critical for its guidance functions.
- These interactions regulate neuronal progenitor cell migration during development.
- The findings provide mechanistic insights into Sema5A-associated disorders and proteoglycan-mediated regulation of guidance cues.
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