8CKM

Semaphorin-5A TSR 3-4 domains

8CKM の概要

• エントリーDOI: 10.2210/pdb8ckm/pdb
• 関連するPDBエントリー: 8CKG 8CKK 8CKL
• 分子名称: Semaphorin-5A (1 entity in total)
• 機能のキーワード: semaphorin, cell signalling, axon guidance cue, glycosaminoglycan binding protein, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28109.40

構造登録者

Nagy, G.N.,Duman, R.,Harlos, K.,El Omari, K.,Wagner, A.,Jones, E.Y. (登録日: 2023-02-15, 公開日: 2024-02-28, 最終更新日: 2024-09-11)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.72 Å)