title: The light chains of kinesin-1 are autoinhibited.
abstract: The light chains (KLCs) of the microtubule motor kinesin-1 bind cargoes and regulate its activity. Through their tetratricopeptide repeat domain (KLC(TPR)), 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.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Yan Y
authors.initials: YY
authors.lastname: Yip
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pernigo
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Anneri
authors.initials: A
authors.lastname: Sanger
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Mengjia
authors.initials: M
authors.lastname: Xu
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom mark.dodding@kcl.ac.uk roberto.steiner@kcl.ac.uk.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Steiner
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom mark.dodding@kcl.ac.uk roberto.steiner@kcl.ac.uk.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Dodding
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid
chemical_list: C488101:KIF5B protein, human; D016547:Kinesins
keywords: KLC; TPR domain; cytoskeleton; kinesin; microtubule motor