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SHANK3 conformation regulates direct actin binding and crosstalk with Rap1 signaling

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SHANK3 conformation regulates direct actin binding and crosstalk with Rap1 signaling. / Salomaa, Siiri I; Miihkinen, Mitro; Kremneva, Elena; Paatero, Ilkka; Lilja, Johanna; Jacquemet, Guillaume; Vuorio, Joni; Antenucci, Lina; Kogan, Konstantin; Hassani Nia, Fatemeh; Hollos, Patrik; Isomursu, Aleksi; Vattulainen, Ilpo; Coffey, Eleanor T; Kreienkamp, Hans-Jürgen; Lappalainen, Pekka; Ivaska, Johanna.

In: CURR BIOL, Vol. 31, No. 22, 22.11.2021, p. 4956-4970.e9.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Salomaa, SI, Miihkinen, M, Kremneva, E, Paatero, I, Lilja, J, Jacquemet, G, Vuorio, J, Antenucci, L, Kogan, K, Hassani Nia, F, Hollos, P, Isomursu, A, Vattulainen, I, Coffey, ET, Kreienkamp, H-J, Lappalainen, P & Ivaska, J 2021, 'SHANK3 conformation regulates direct actin binding and crosstalk with Rap1 signaling', CURR BIOL, vol. 31, no. 22, pp. 4956-4970.e9. https://doi.org/10.1016/j.cub.2021.09.022

APA

Salomaa, S. I., Miihkinen, M., Kremneva, E., Paatero, I., Lilja, J., Jacquemet, G., Vuorio, J., Antenucci, L., Kogan, K., Hassani Nia, F., Hollos, P., Isomursu, A., Vattulainen, I., Coffey, E. T., Kreienkamp, H-J., Lappalainen, P., & Ivaska, J. (2021). SHANK3 conformation regulates direct actin binding and crosstalk with Rap1 signaling. CURR BIOL, 31(22), 4956-4970.e9. https://doi.org/10.1016/j.cub.2021.09.022

Vancouver

Salomaa SI, Miihkinen M, Kremneva E, Paatero I, Lilja J, Jacquemet G et al. SHANK3 conformation regulates direct actin binding and crosstalk with Rap1 signaling. CURR BIOL. 2021 Nov 22;31(22):4956-4970.e9. https://doi.org/10.1016/j.cub.2021.09.022

Bibtex

@article{efc493eb99884256b00a9709e6de753a,
title = "SHANK3 conformation regulates direct actin binding and crosstalk with Rap1 signaling",
abstract = "Actin-rich cellular protrusions direct versatile biological processes from cancer cell invasion to dendritic spine development. The stability, morphology, and specific biological functions of these protrusions are regulated by crosstalk between three main signaling axes: integrins, actin regulators, and small guanosine triphosphatases (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 Shank/ProSAP N-terminal (SPN) domain. Here, we demonstrate that, in addition to scaffolding actin regulators and actin-binding proteins, SHANK3 interacts directly with actin through its SPN domain. Molecular simulations and targeted mutagenesis of the SPN-ankyrin repeat region (ARR) interface reveal that actin binding is 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 mutation of SHANK3, resulting in reduced actin binding, augments inhibition of Rap1-mediated integrin activity. This dynamic crosstalk has functional implications for cell morphology and integrin activity in cancer cells. In addition, SHANK3-actin interaction regulates dendritic spine morphology in neurons and autism-linked phenotypes in vivo.",
author = "Salomaa, {Siiri I} and Mitro Miihkinen and Elena Kremneva and Ilkka Paatero and Johanna Lilja and Guillaume Jacquemet and Joni Vuorio and Lina Antenucci and Konstantin Kogan and {Hassani Nia}, Fatemeh and Patrik Hollos and Aleksi Isomursu and Ilpo Vattulainen and Coffey, {Eleanor T} and Hans-J{\"u}rgen Kreienkamp and Pekka Lappalainen and Johanna Ivaska",
note = "Copyright {\textcopyright} 2021 Elsevier Inc. All rights reserved.",
year = "2021",
month = nov,
day = "22",
doi = "10.1016/j.cub.2021.09.022",
language = "English",
volume = "31",
pages = "4956--4970.e9",
journal = "CURR BIOL",
issn = "0960-9822",
publisher = "Cell Press",
number = "22",

}

RIS

TY - JOUR

T1 - SHANK3 conformation regulates direct actin binding and crosstalk with Rap1 signaling

AU - Salomaa, Siiri I

AU - Miihkinen, Mitro

AU - Kremneva, Elena

AU - Paatero, Ilkka

AU - Lilja, Johanna

AU - Jacquemet, Guillaume

AU - Vuorio, Joni

AU - Antenucci, Lina

AU - Kogan, Konstantin

AU - Hassani Nia, Fatemeh

AU - Hollos, Patrik

AU - Isomursu, Aleksi

AU - Vattulainen, Ilpo

AU - Coffey, Eleanor T

AU - Kreienkamp, Hans-Jürgen

AU - Lappalainen, Pekka

AU - Ivaska, Johanna

N1 - Copyright © 2021 Elsevier Inc. All rights reserved.

PY - 2021/11/22

Y1 - 2021/11/22

N2 - Actin-rich cellular protrusions direct versatile biological processes from cancer cell invasion to dendritic spine development. The stability, morphology, and specific biological functions of these protrusions are regulated by crosstalk between three main signaling axes: integrins, actin regulators, and small guanosine triphosphatases (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 Shank/ProSAP N-terminal (SPN) domain. Here, we demonstrate that, in addition to scaffolding actin regulators and actin-binding proteins, SHANK3 interacts directly with actin through its SPN domain. Molecular simulations and targeted mutagenesis of the SPN-ankyrin repeat region (ARR) interface reveal that actin binding is 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 mutation of SHANK3, resulting in reduced actin binding, augments inhibition of Rap1-mediated integrin activity. This dynamic crosstalk has functional implications for cell morphology and integrin activity in cancer cells. In addition, SHANK3-actin interaction regulates dendritic spine morphology in neurons and autism-linked phenotypes in vivo.

AB - Actin-rich cellular protrusions direct versatile biological processes from cancer cell invasion to dendritic spine development. The stability, morphology, and specific biological functions of these protrusions are regulated by crosstalk between three main signaling axes: integrins, actin regulators, and small guanosine triphosphatases (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 Shank/ProSAP N-terminal (SPN) domain. Here, we demonstrate that, in addition to scaffolding actin regulators and actin-binding proteins, SHANK3 interacts directly with actin through its SPN domain. Molecular simulations and targeted mutagenesis of the SPN-ankyrin repeat region (ARR) interface reveal that actin binding is 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 mutation of SHANK3, resulting in reduced actin binding, augments inhibition of Rap1-mediated integrin activity. This dynamic crosstalk has functional implications for cell morphology and integrin activity in cancer cells. In addition, SHANK3-actin interaction regulates dendritic spine morphology in neurons and autism-linked phenotypes in vivo.

U2 - 10.1016/j.cub.2021.09.022

DO - 10.1016/j.cub.2021.09.022

M3 - SCORING: Journal article

C2 - 34610274

VL - 31

SP - 4956-4970.e9

JO - CURR BIOL

JF - CURR BIOL

SN - 0960-9822

IS - 22

ER -