Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 52, Pages 13738-13743Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1715115115
Keywords
kinesin-1; microtubule dynamics; kinesore; small molecule; intracellular transport
Categories
Funding
- Wellcome Trust Research Career Development Fellowship [097316/Z/11/Z]
- Biotechnology and Biological Sciences Research Council project [BB/L006774/1]
- UK Medical Research Council Grant [MR/K015664/1]
- Asthma UK [09/029]
- Wellcome Trust [097316/Z/11/Z] Funding Source: Wellcome Trust
- Biotechnology and Biological Sciences Research Council [BB/L006774/1] Funding Source: researchfish
- Medical Research Council [MR/K015664/1] Funding Source: researchfish
- BBSRC [BB/L006774/1] Funding Source: UKRI
- MRC [MR/K015664/1] Funding Source: UKRI
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The microtubule motor kinesin-1 interacts via its cargo-binding domain with both microtubules and organelles, and hence plays an important role in controlling organelle transport and microtubule dynamics. In the absence of cargo, kinesin-1 is found in an auto-inhibited conformation. The molecular basis of how cargo engagement affects the balance between kinesin-1's active and inactive conformations and roles in microtubule dynamics and organelle transport is not well understood. Here we describe the discovery of kinesore, a small molecule that in vitro inhibits kinesin-1 interactions with short linear peptide motifs found in organelle-specific cargo adaptors, yet activates kinesin-1's function of controlling microtubule dynamics in cells, demonstrating that these functions are mechanistically coupled. We establish a proof-of-concept that a microtubule motor-cargo interface and associated autoregulatory mechanism can be manipulated using a small molecule, and define a target for the modulation of microtubule dynamics.
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