Structure and function of Semaphorin-5A glycosaminoglycan interactions
dc.contributor.author | Nagy, GN | |
dc.contributor.author | Zhao, XF | |
dc.contributor.author | Karlsson, R | |
dc.contributor.author | Wang, K | |
dc.contributor.author | Duman, R | |
dc.contributor.author | Harlos, K | |
dc.contributor.author | El Omari, K | |
dc.contributor.author | Wagner, A | |
dc.contributor.author | Clausen, H | |
dc.contributor.author | Miller, RL | |
dc.contributor.author | Giger, RJ | |
dc.contributor.author | Jones, EY | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2024-05-21T15:11:16Z | |
dc.date.available | 2024-05-21T15:11:16Z | |
dc.date.issued | 2024-12-01 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://www.ncbi.nlm.nih.gov/pubmed/38548715 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/193165 | en |
dc.description.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. | |
dc.format.medium | Electronic | |
dc.language | eng | |
dc.publisher | Springer Nature | |
dc.relation.haspart | 2723 | |
dc.rights | Licence for published version: Creative Commons Attribution 4.0 International | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Glycosaminoglycans | |
dc.subject | Proteoglycans | |
dc.subject | Heparitin Sulfate | |
dc.subject | Cell Movement | |
dc.subject | Semaphorins | |
dc.title | Structure and function of Semaphorin-5A glycosaminoglycan interactions | |
dc.type | Article | |
dc.identifier.pmid | 38548715 | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/193165/2/Structure and function of Semaphorin-5A glycosaminoglycan interactions.pdf | |
dc.identifier.doi | 10.1038/s41467-024-46725-7 | |
dc.identifier.doi | https://dx.doi.org/10.7302/22810 | |
dc.identifier.source | Nature Communications | |
dc.description.version | Accepted version | |
dc.date.updated | 2024-05-21T15:11:11Z | |
dc.identifier.orcid | 0000-0003-1761-5610 | |
dc.identifier.orcid | 0000-0002-7574-7163 | |
dc.identifier.orcid | 0000-0003-0448-6135 | |
dc.identifier.orcid | 0000-0003-3506-6045 | |
dc.identifier.orcid | 0000-0001-8995-7324 | |
dc.identifier.orcid | 0000-0002-0915-5055 | |
dc.identifier.orcid | 0000-0001-8574-1948 | |
dc.identifier.orcid | 0000-0002-2926-3336 | |
dc.identifier.orcid | 0000-0002-3834-1893 | |
dc.description.filedescription | Description of Structure and function of Semaphorin-5A glycosaminoglycan interactions.pdf : Published version | |
dc.identifier.volume | 15 | |
dc.identifier.issue | 1 | |
dc.identifier.startpage | 2723 | |
dc.identifier.name-orcid | Nagy, GN; 0000-0003-1761-5610 | |
dc.identifier.name-orcid | Zhao, XF; 0000-0002-7574-7163 | |
dc.identifier.name-orcid | Karlsson, R; 0000-0003-0448-6135 | |
dc.identifier.name-orcid | Wang, K | |
dc.identifier.name-orcid | Duman, R | |
dc.identifier.name-orcid | Harlos, K | |
dc.identifier.name-orcid | El Omari, K; 0000-0003-3506-6045 | |
dc.identifier.name-orcid | Wagner, A; 0000-0001-8995-7324 | |
dc.identifier.name-orcid | Clausen, H; 0000-0002-0915-5055 | |
dc.identifier.name-orcid | Miller, RL; 0000-0001-8574-1948 | |
dc.identifier.name-orcid | Giger, RJ; 0000-0002-2926-3336 | |
dc.identifier.name-orcid | Jones, EY; 0000-0002-3834-1893 | |
dc.working.doi | 10.7302/22810 | en |
dc.owningcollname | Molecular and Behavioral Neurosciences Institute |
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