Myosin 1c (Myo1c) plays a key role in supporting motile events that underlie
cell migration, vesicle trafficking, insulin-stimulated glucose uptake and
hearing. Here, we present the crystal structure of the human Myo1c motor in
complex with its light chain calmodulin. Our structure reveals tight
interactions of the motor domain with calmodulin bound to the first IQ motif in
the neck region. Several of the calmodulin residues contributing to this
interaction are also involved in Ca(2+) binding. Contact residues in the motor
domain are linked to the central β-sheet and the HO helix, suggesting a
mechanism for communicating changes in Ca(2+) binding in the neck region to the
actin and nucleotide binding regions of the motor domain. The structural context
and the chemical environment of Myo1c mutations that are involved in
sensorineural hearing loss in humans are described and their impact on motor
function is discussed. We show that a construct consisting of the motor domain
of Myo1c and the first IQ motif is sufficient to establish a tight interaction
with 14-3-3β (KD=0.9μM) and present the model of a double-headed Myo1c-14-3-3
complex. This complex has been implicated in the exocytosis of glucose
transporter 4 storage vesicles during insulin-stimulated glucose uptake.
