Journal article
Structure and function of Semaphorin-5A glycosaminoglycan interactions
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 4.0MB, Terms of use)
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- Publisher copy:
- 10.1038/s41467-024-46725-7
Authors
+ Novo Nordisk Fonden
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- Funder identifier:
- 10.13039/501100009708
- Grant:
- NNF22OC0073736
+ RCUK | Medical Research Council
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- Funder identifier:
- 10.13039/501100000265
- Grant:
- MR/T000503/1
+ U.S. Department of Health & Human Services | National Institutes of Health
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- Funder identifier:
- 10.13039/100000002
- Grant:
- R01 MH119346
- Publisher:
- Nature Research
- Journal:
- Nature Communications More from this journal
- Volume:
- 15
- Issue:
- 1
- Pages:
- 2723-2723
- Article number:
- 2723
- Publication date:
- 2024-03-28
- DOI:
- EISSN:
-
2041-1723
- ISSN:
-
2041-1723
- Language:
-
English
- Keywords:
- Pubs id:
-
1924966
- Local pid:
-
pubs:1924966
- Source identifiers:
-
W4393258643
- Deposit date:
-
2026-06-10
- ARK identifier:
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Terms of use
- Copyright date:
- 2024
- Licence:
- CC Attribution (CC BY)
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