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.
Deciphering the Molecular Terms of Arp2/3 Allosteric Regulation from All-Atom Simulations and Dynamical Network Theory / Laporte, S.; Magistrato, A.. - In: THE JOURNAL OF PHYSICAL CHEMISTRY LETTERS. - ISSN 1948-7185. - 12:22(2021), pp. 5384-5389. [10.1021/acs.jpclett.1c00940]
Deciphering the Molecular Terms of Arp2/3 Allosteric Regulation from All-Atom Simulations and Dynamical Network Theory
Laporte, S.;Magistrato, A.
2021-01-01
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.