Multi-Pole Approach to Structural Science

May 10 - 13, 2015

The structural biology of Ca2+-independent modulation of smooth muscle contraction
Zygmunt Derewenda, Avril V. Somlyo

It is well established that smooth muscle contraction is initiated by the influx of Ca ions, leading to the activation of the myosin light chain kinase (MLCK) and the canonical cross-bridge cycle. However, during the last two decades, intense research revealed that this simple mechanism is tuned and modulated in each smooth muscle tissue, specifically through the so-called Ca-sensitization effect, whereby contraction is sustained as Ca-levels drop, due to the inhibition of the myosin light chain phosphatase. This process is controlled by agonists that activate G-protein coupled receptors, which in turn engage the small GTPase RhoA. A plethora of accessory proteins, that either up- or down-regulate RhoA may confer tissue-specficity on numerous regulatory phenomena. These proteins potentially offer new targets for the discovery of drugs that could more selectively and specifically control such disease states as hypertension and asthma. Our laboratories collaborated for over twenty years on the elucidation of physiology and structural biology of the regulation of RhoA. This led, among others, to the determination of the first crystal structure of RhoA, and a number of regulatory proteins including GAPs (GTPase activating proteins), GEFs (Guanine exchange factors) and RhoGDI (the guanine nucleotide-dissociation inhibitor). This presentation will review these studies and introduce new avenues, currently under investigation in our laboratories.