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7e2h

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Cryo-EM structure of hDisp1NNN-3C-Cleavage

Structural highlights

7e2h is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.68Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DISP1_HUMAN Septopreoptic holoprosencephaly;Alobar holoprosencephaly;Semilobar holoprosencephaly;Lobar holoprosencephaly;Midline interhemispheric variant of holoprosencephaly;Microform holoprosencephaly.

Function

DISP1_HUMAN Functions in hedgehog (Hh) signaling. Regulates the release and extracellular accumulation of cholesterol-modified hedgehog proteins and is hence required for effective production of the Hh signal (By similarity). Synergizes with SCUBE2 to cause an increase in SHH secretion (PubMed:22902404).[UniProtKB:Q3TDN0]^[1]

Publication Abstract from PubMed

The membrane protein Dispatched (Disp), which belongs to the RND family of small molecule transporters, is essential for Hedgehog (Hh) signaling, by catalyzing the extracellular release of palmitate- and cholesterol-modified Hh ligands from producing cells. Disp function requires Furin-mediated proteolytic cleavage of its extracellular domain, but how this activates Disp remains obscure. Here, we employ cryo-electron microscopy to determine atomic structures of human Disp1 (hDisp1), before and after cleavage, and in complex with lipid-modified Sonic hedgehog (Shh) ligand. These structures, together with biochemical data, reveal that proteolytic cleavage opens the extracellular domain of hDisp1, removing steric hindrance to Shh binding. Structure-guided functional experiments demonstrate the role of hDisp1-Shh interactions in ligand release. Our results clarify the mechanisms of hDisp1 activation and Shh morphogen release, and highlight how a unique proteolytic cleavage event enabled acquisition of a protein substrate by a member of a family of small molecule transporters.

Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release.,Li W, Wang L, Wierbowski BM, Lu M, Dong F, Liu W, Li S, Wang P, Salic A, Gong X Nat Commun. 2021 Nov 29;12(1):6966. doi: 10.1038/s41467-021-27257-w. PMID:34845226^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tukachinsky H, Kuzmickas RP, Jao CY, Liu J, Salic A. Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand. Cell Rep. 2012 Aug 30;2(2):308-20. doi: 10.1016/j.celrep.2012.07.010. Epub 2012, Aug 16. PMID:22902404 doi:http://dx.doi.org/10.1016/j.celrep.2012.07.010
↑ Li W, Wang L, Wierbowski BM, Lu M, Dong F, Liu W, Li S, Wang P, Salic A, Gong X. Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release. Nat Commun. 2021 Nov 29;12(1):6966. PMID:34845226 doi:10.1038/s41467-021-27257-w