8CKL

Semaphorin-5A TSR 3-4 domains in complex with sucrose octasulfate (SOS)

Summary for 8CKL

• Entry DOI: 10.2210/pdb8ckl/pdb
• Related: 8CKG 8CKK 8CKM
• Related PRD ID: PRD_900013
• Descriptor: Semaphorin-5A, 2,3,4,6-tetra-O-sulfonato-alpha-D-glucopyranose-(1-2)-1,3,4,6-tetra-O-sulfo-beta-D-fructofuranose, alpha-D-mannopyranose (3 entities in total)
• Functional Keywords: semaphorin, cell signalling, axon guidance cue, glycosaminoglycan binding protein, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 29812.83

Authors

Nagy, G.N.,Duman, R.,Harlos, K.,El Omari, K.,Wagner, A.,Jones, E.Y. (deposition date: 2023-02-15, release date: 2024-02-28, Last modification date: 2024-10-23)

Primary citation

Nagy, G.N.,Zhao, X.F.,Karlsson, R.,Wang, K.,Duman, R.,Harlos, K.,El Omari, K.,Wagner, A.,Clausen, H.,Miller, R.L.,Giger, R.J.,Jones, E.Y.
Structure and function of Semaphorin-5A glycosaminoglycan interactions.
Nat Commun, 15:2723-2723, 2024

PubMed 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.

PubMed: 38548715
DOI: 10.1038/s41467-024-46725-7

Experimental method

X-RAY DIFFRACTION (2.56 Å)