Structural study points to membrane feedback that amplifies Cdc42 activation

Activated Cdc42 binds a separate domain

Using cryo-electron microscopy, artificial lipid membranes, biochemical experiments and cell experiments, the group examined complexes of DOCK11 and Cdc42.

It reported that activated Cdc42 binds directly to DOCK11’s ARM domain, distinct from the DHR2 catalytic domain that acts on inactive Cdc42. In artificial membrane experiments, membrane-bound activated Cdc42 was associated with about a 2.5-fold increase in DOCK11’s Cdc42-activating activity; the reported effect was not seen when activated Cdc42 was not membrane-bound.

The molecular-level binding site for activated Cdc42 on DOCK11, and how that binding enhanced DOCK11 activity, had been described as unknown.

The group reported identifying activated Cdc42 binding at DOCK11’s ARM domain and a membrane-associated structural arrangement that they say stabilizes DOCK11 and promotes further Cdc42 activation.

Membrane binding is a condition for the effect

The reported model explains how a product of DOCK11 activity—activated Cdc42—could reinforce further activation at a cell membrane through positive feedback. The group says the findings may provide a basis for understanding molecular mechanisms of conditions involving DOCK11 and for future drug-discovery research, rather than establishing a treatment.