Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 27, Pages 8320-8325Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1510094112
Keywords
Hedgehog signaling; primary cilia; Smoothened; single-molecule microscopy; single-particle tracking
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Funding
- Stanford Bio-X Interdisciplinary Initiatives Seed Grant
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences [R01GM086196, R01GM085437]
- National Institutes of Health National Eye Institute [PN2EY016525]
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Accumulation of the signaling protein Smoothened (Smo) in the membrane of primary cilia is an essential step in Hedgehog (Hh) signal transduction, yet the molecular mechanisms of Smo movement and localization are poorly understood. Using ultrasensitive single-molecule tracking with high spatial/temporal precision (30 nm/10 ms), we discovered that binding events disrupt the primarily diffusive movement of Smo in cilia at an array of sites near the base. The affinity of Smo for these binding sites was modulated by the Hh pathway activation state. Activation, by either a ligand or genetic loss of the negatively acting Hh receptor Patched-1 (Ptch), reduced the affinity and frequency of Smo binding at the base. Our findings quantify activation-dependent changes in Smo dynamics in cilia and highlight a previously unknown step in Hh pathway activation.
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