Patched 1 reduces the accessibility of cholesterol in the outer leaflet of membranes.
cell biology
cholesterol
cholesterol accessibility
developmental biology
hedgehog signaling
ion gradient
membrane biology
membrane protein
mouse
patched
primary cilia
smoothened
transporter
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
26 10 2021
26 10 2021
Historique:
received:
27
05
2021
accepted:
25
10
2021
pubmed:
27
10
2021
medline:
27
1
2022
entrez:
26
10
2021
Statut:
epublish
Résumé
A long-standing mystery in vertebrate Hedgehog signaling is how Patched 1 (PTCH1), the receptor for Hedgehog ligands, inhibits the activity of Smoothened, the protein that transmits the signal across the membrane. We previously proposed (Kinnebrew et al., 2019) that PTCH1 inhibits Smoothened by depleting accessible cholesterol from the ciliary membrane. Using a new imaging-based assay to directly measure the transport activity of PTCH1, we find that PTCH1 depletes accessible cholesterol from the outer leaflet of the plasma membrane. This transport activity is terminated by binding of Hedgehog ligands to PTCH1 or by dissipation of the transmembrane potassium gradient. These results point to the unexpected model that PTCH1 moves cholesterol from the outer to the inner leaflet of the membrane in exchange for potassium ion export in the opposite direction. Our study provides a plausible solution for how PTCH1 inhibits SMO by changing the organization of cholesterol in membranes and establishes a general framework for studying how proteins change cholesterol accessibility to regulate membrane-dependent processes in cells.
Identifiants
pubmed: 34698632
doi: 10.7554/eLife.70504
pii: 70504
pmc: PMC8654371
doi:
pii:
Substances chimiques
PTCH1 protein, human
0
Patched-1 Receptor
0
SMO protein, human
0
Smoothened Receptor
0
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL020948
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118082
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM106078
Pays : United States
Organisme : European Research Council
ID : 647278
Pays : International
Organisme : Cancer Research UK
ID : C20724
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A26752
Pays : United Kingdom
Informations de copyright
© 2021, Kinnebrew et al.
Déclaration de conflit d'intérêts
MK, GL, RS, SF, LV, TN, FB, YS, CS, RR No competing interests declared, AR is a reviewing editor for eLife
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