RT Journal Article SR Electronic T1 Conformational dynamics regulate SHANK3 actin and Rap1 binding JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.11.12.379222 DO 10.1101/2020.11.12.379222 A1 Siiri I Salomaa A1 Mitro Miihkinen A1 Elena Kremneva A1 Ilkka Paatero A1 Johanna Lilja A1 Guillaume Jacquemet A1 Joni Vuorio A1 Lina Antenucci A1 Fatemeh Hassani-Nia A1 Patrik Hollos A1 Aleksi Isomursu A1 Ilpo Vattulainen A1 Eleanor T. Coffey A1 Hans-Jürgen Kreienkamp A1 Pekka Lappalainen A1 Johanna Ivaska YR 2020 UL http://biorxiv.org/content/early/2020/11/12/2020.11.12.379222.abstract AB Actin-rich cellular protrusions direct versatile biological processes from cancer cell invasion to dendritic spine development. The stability, morphology and specific biological function of these protrusions are regulated by crosstalk between three main signaling axes: integrins, actin regulators and small GTPases. SHANK3 is a multifunctional scaffold protein, interacting with several actin-binding proteins, and a well-established autism risk gene. Recently, SHANK3 was demonstrated to sequester integrin-activating small GTPases Rap1 and R-Ras to inhibit integrin activity via its N-terminal SPN domain. Here, we demonstrate that SHANK3 interacts directly with actin using its SPN domain. Actin binding can be inhibited by an intramolecular closed conformation of SHANK3, where the adjacent ARR domain covers the actin-binding interface of the SPN domain. Actin and Rap1 compete with each other for binding to SHANK3 and loss of SHANK3-actin binding augments inhibition of Rap1-mediated integrin activity. This dynamic crosstalk has functional implications for filopodia formation in cancer cells, dendritic spine morphology in neurons and autism-linked phenotypes in vivo.Competing Interest StatementThe authors have declared no competing interest.