Anillin: The First Proofreading-like Scaffold?

Scaffolds are fundamental to many cellular signaling pathways. In this essay, a novel class of scaffolds are proposed, whose action bears striking resemblance to kinetic proofreading. Commonly, scaffold proteins are thought to work as tethers, bringing different components of a pathway together to improve the likelihood of their interaction. However, recent studies show that the cytoskeletal scaffold, anillin, supports contractile signaling by a novel, non-tethering mechanism that controls the membrane dissociation kinetics of RhoA. More generally, such proof-reading-like scaffolds are distinguished from tethers by a rare type of cooperativity, manifest as a super-linear relationship between scaffold concentration and signaling efficiency. The evidence for this hypothesis is reviewed, its conceptual ramifications are considered, and research questions for the future are discussed.

Anillin Promotes Cell Contractility by Cyclic Resetting of RhoA Residence Kinetics.

RhoA stimulates cell contractility by recruiting downstream effectors to the cortical plasma membrane. We now show that direct binding by anillin is required for effective signaling: this antagonizes the otherwise labile membrane association of GTP-RhoA to promote effector recruitment. However, since its binding to RhoA blocks access by other effectors, we demonstrate that anillin must also concentrate membrane phosphoinositide-4,5-P2 (PIP2) to promote signaling. We propose and test a sequential pathway where GTP-RhoA first binds to anillin and then is retained at the membrane by PIP2 after it disengages from anillin. Importantly, re-binding of membrane GTP-RhoA to anillin, regulated by the cortical density of anillin, creates cycles through this pathway. These cycles repeatedly reset the dissociation kinetics of GTP-RhoA, substantially increasing its dwell time to recruit effectors. Thus, anillin regulates RhoA signaling by a paradigm of kinetic scaffolding that may apply to other signals whose efficacy depends on their cortical dwell times.