Associations between the Rho kinase-1 catalytic and PH domain regulatory unit

• Rho associated kinase-1, ROCK1, is an important drug target in heart disease, specifically in pathophysiological cardiac hypertrophy and reactive fibrosis and cardiac remodeling.
• ROCK1 is proposed to be autoregulated by its Pleckstrin-Homology domain (PH domain) possibly by the formation of a complex.
• We show that ROCK1 and its PH domain associate from measurements using surface plasmon resonance.
• Computation docking of both the PH domain and the C1 domain insert find complementary interfaces on the ROCK1 catalytic domain.
• All three domains have computational viable clusters in a three member complex.

Rho-associated kinase, or ROCK, is an important mediator of ventricular remodeling in cardiac hypertrophy. It has a kinase catalytic domain, a coiled–coil domain and a Pleckstrin-Homology domain (PH domain) with a C1 domain insert. The C-terminal region including the PH domain and C1 domain insert is involved in an autoregulatory role for ROCK. We sought to evaluate whether a self association complex could form using computational docking approaches. We found that both the PH domain and the C1 domain could dock with the catalytic domain and we further found that they could dock in poses that are complementary to each other forming a three domain complex. We also confirmed a binding response using a surface plasmon resonance experimental approach. Information about the regulation of ROCK might lead to new strategies to develop lead inhibitor compounds to modulate cardiac remodeling.

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