We present a model for the skeletal muscle troponin-C
(TnC)/troponin-I (TnI) interaction, a critical molecular
switch that is responsible for calcium-dependent regulation
of the contractile mechanism. Despite concerted efforts
by multiple groups for more than a decade, attempts to
crystallize troponin-C in complex with troponin-I, or in
the ternary troponin complex, have not yet delivered a
high-resolution structure. Many groups have pursued different
experimental strategies, such as X-ray crystallography,
NMR, small-angle scattering, chemical cross-linking, and
fluorescent resonance energy transfer (FRET) to gain insights
into the nature of the TnC/TnI interaction. We have integrated
the results of these experiments to develop a model of
the TnC/TnI interaction, using an atomic model of TnC as
a scaffold. The TnI sequence was fit to each of two alternate
neutron scattering envelopes: one that winds about TnC
in a left-handed sense (Model L), and another that winds
about TnC in a right-handed sense (Model R). Information
from crystallography and NMR experiments was used to define
segments of the models. Tests show that both models are
consistent with available cross-linking and FRET data.
The inhibitory region TnI(95–114) is modeled as a
flexible β-hairpin, and in both models it is localized
to the same region on the central helix of TnC. The sequence
of the inhibitory region is similar to that of a β-hairpin
region of the actin-binding protein profilin. This similarity
supports our model and suggests the possibility of using
an available profilin/actin crystal structure to model
the TnI/actin interaction. We propose that the β-hairpin
is an important structural motif that communicates the
Ca2+-activated troponin regulatory signal to actin.