7RPK

Cryo-EM structure of murine Dispatched in complex with Sonic hedgehog

7RPK の概要

• エントリーDOI: 10.2210/pdb7rpk/pdb
• EMDBエントリー: 24614 24615 24616 24617
• 分子名称: Protein dispatched homolog 1, SULFATE ION, Sonic hedgehog protein, ... (11 entities in total)
• 機能のキーワード: rnd transporter, hedgehog binding, sterol sensing domain, sodium binding, membrane protein
• 由来する生物種: Mus musculus (Mouse); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 187273.56

構造登録者

Asarnow, D.,Wang, Q.,Ding, K.,Cheng, Y.,Beachy, P.A. (登録日: 2021-08-03, 公開日: 2021-10-27, 最終更新日: 2024-11-13)

主引用文献

Wang, Q.,Asarnow, D.E.,Ding, K.,Mann, R.K.,Hatakeyama, J.,Zhang, Y.,Ma, Y.,Cheng, Y.,Beachy, P.A.
Dispatched uses Na + flux to power release of lipid-modified Hedgehog.
Nature, 599:320-324, 2021

PubMed Abstract: The Dispatched protein, which is related to the NPC1 and PTCH1 cholesterol transporters and to H-driven transporters of the RND family, enables tissue-patterning activity of the lipid-modified Hedgehog protein by releasing it from tightly -localized sites of embryonic expression. Here we determine a cryo-electron microscopy structure of the mouse protein Dispatched homologue 1 (DISP1), revealing three Na ions coordinated within a channel that traverses its transmembrane domain. We find that the rate of Hedgehog export is dependent on the Na gradient across the plasma membrane. The transmembrane channel and Na binding are disrupted in DISP1-NNN, a variant with asparagine substitutions for three intramembrane aspartate residues that each coordinate and neutralize the charge of one of the three Na ions. DISP1-NNN and variants that disrupt single Na sites retain binding to, but are impaired in export of the lipid-modified Hedgehog protein to the SCUBE2 acceptor. Interaction of the amino-terminal signalling domain of the Sonic hedgehog protein (ShhN) with DISP1 occurs via an extensive buried surface area and contacts with an extended furin-cleaved DISP1 arm. Variability analysis reveals that ShhN binding is restricted to one extreme of a continuous series of DISP1 conformations. The bound and unbound DISP1 conformations display distinct Na-site occupancies, which suggests a mechanism by which transmembrane Na flux may power extraction of the lipid-linked Hedgehog signal from the membrane. Na-coordinating residues in DISP1 are conserved in PTCH1 and other metazoan RND family members, suggesting that Na flux powers their conformationally driven activities.

PubMed: 34707294
DOI: 10.1038/s41586-021-03996-0

実験手法

ELECTRON MICROSCOPY (2.7 Å)