TY - JOUR
T1 - Structure of human Dispatched-1 provides insights into Hedgehog ligand biogenesis
AU - Chen, Hongwen
AU - Liu, Yang
AU - Li, Xiaochun
N1 - Funding Information:
We thank D Stoddard at the University of Texas (UT) Southwestern Medical Center Cryo-EM Facility (funded in part by the CPRIT Core Facility Support Award RP170644) for assistance in data collection. We thank P Beachy for sharing the Disp1−/− MEFs and stable cell line for SCUBE2 expression; V Korkhov for structure coordinates of dDISP1 prior to publication; and R DeBose-Boyd, E Debler, L Friedburg, T Long, and X Qi for manuscript preparation. This work was supported by the Endowed Scholars Program in Medical Science of UT Southwestern Medical Center, National Institutes of Health (NIH) grant P01 HL020948, NIH grant R01 GM135343 (to X Li). X Li is a Damon Runyon-Rachleff Innovator supported by the Damon Runyon Cancer Research Foundation (DRR-53-19) and a Rita C. and William P. Clements Jr. Scholar in Biomedical Research at UT Southwestern Medical Center.
Publisher Copyright:
© 2020 Chen et al.
PY - 2020
Y1 - 2020
N2 - Hedgehog (HH) signaling is essential for metazoan development. The HH ligand is secreted into the extracellular space by a cell surface protein named Dispatched-1 (DISP1). Here, we report the cryo-EM structure of human DISP1 protein. DISP1 contains 12 transmembrane helices (TMs) and two extracellular domains (ECDs). Its ECDs reveal an open state, in contrast to its structural homologues PTCH1 and NPC1, whose extracellular/luminal domains adopt a closed state. The low-resolution structure of the DISP1 complex with dual lipid-modified HH ligand reveals how the ECDs of DISP1 engage with HH ligand. Moreover, several cholesterol-like molecules are found in the TMs, implying a transport-like function of DISP1.
AB - Hedgehog (HH) signaling is essential for metazoan development. The HH ligand is secreted into the extracellular space by a cell surface protein named Dispatched-1 (DISP1). Here, we report the cryo-EM structure of human DISP1 protein. DISP1 contains 12 transmembrane helices (TMs) and two extracellular domains (ECDs). Its ECDs reveal an open state, in contrast to its structural homologues PTCH1 and NPC1, whose extracellular/luminal domains adopt a closed state. The low-resolution structure of the DISP1 complex with dual lipid-modified HH ligand reveals how the ECDs of DISP1 engage with HH ligand. Moreover, several cholesterol-like molecules are found in the TMs, implying a transport-like function of DISP1.
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U2 - 10.26508/LSA.202000776
DO - 10.26508/LSA.202000776
M3 - Article
C2 - 32646883
AN - SCOPUS:85087841329
SN - 2575-1077
VL - 3
JO - Life Science Alliance
JF - Life Science Alliance
IS - 8
M1 - e202000776
ER -