Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 9, Pages 2418-2423Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1520817113
Keywords
kinesin; KLC; TPR domain; microtubule motor; cytoskeleton
Categories
Funding
- Biotechnology and Biological Sciences Research Council [BB/L006774/1]
- Wellcome Trust Research Career Development Fellowship
- London Law Trust Medal Fellowship
- BBSRC [BB/L006774/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/L006774/1] Funding Source: researchfish
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The light chains (KLCs) of the microtubule motor kinesin-1 bind cargoes and regulate its activity. Through their tetratricopeptide repeat domain (KLCTPR), they can recognize short linear peptide motifs found in many cargo proteins characterized by a central tryptophan flanked by aspartic/glutamic acid residues (W-acidic). Using a fluorescence resonance energy transfer biosensor in combination with X-ray crystallographic, biochemical, and biophysical approaches, we describe how an intramolecular interaction between the KLC2(TPR) domain and a conserved peptide motif within an unstructured region of the molecule, partly occludes the W-acidic binding site on the TPR domain. Cargo binding displaces this interaction, effecting a global conformational change in KLCs resulting in a more extended conformation. Thus, like the motor-bearing kinesin heavy chains, KLCs exist in a dynamic conformational state that is regulated by self-interaction and cargo binding. We propose a model by which, via this molecular switch, W-acidic cargo binding regulates the activity of the holoenzyme.
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