posted on 2021-06-02, 18:36authored bySara Laporte, Alessandra Magistrato
The
Arp2/3 molecular machine stimulates the generation of branched
actin networks at the cytosolic surface of cellular membranes. Arp2/3
is thus pivotal for cell motility and migration, and its aberrant
function is implicated in cancer invasion and metastasis. Here, all-atom
multi μs-long molecular dynamics simulations and dynamical NetWork
Analysis (NWA) unprecedentedly disclose the molecular terms of Arp2/3
regulation (activation/inhibition) by positive/negative allosteric
modulators. After identifying the crucial structural elements underlying
Arp2/3′s conformational transition toward its active actin-polymerization-competent
state, we decrypt the activating signaling paths heading from the
allosteric effector (ATP) binding sites to these pivotal regions,
also elucidating how small-molecule inhibitors scramble this signal-exchange.
As a result, while ATP-induced signaling triggers a harmonious conformational
transition toward active Arp2/3, the inhibitors disturb these information
channels, desynchronizing Arp2/3 functional movements, thus hindering
its activation. Our outcomes supply a conceptual basis for devising
small-molecule inhibitors to block infiltrative cancer migration.