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Scaffolding of RhoA contractile signaling by anillin: a regulatory analogue of kinetic proofreading

View ORCID ProfileSrikanth Budnar, Kabir B. Husain, Guillermo A. Gomez, Maedeh Naghibosidat, Suzie Verma, Nicholas A. Hamilton, Richard G. Morris, View ORCID ProfileAlpha S. Yap
doi: https://doi.org/10.1101/282756
Srikanth Budnar
1Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Queensland, Australia 4072
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  • For correspondence: s.budnar@imb.uq.edu.au richardgm@ncbs.res.in
Kabir B. Husain
2Simons Centre for the Study of Living Machines, National Centre for Biological Sciences, Tata Institute for Fundamental Research, 560065 Bangalore, India
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Guillermo A. Gomez
1Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Queensland, Australia 4072
3Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5000
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Maedeh Naghibosidat
1Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Queensland, Australia 4072
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Suzie Verma
1Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Queensland, Australia 4072
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Nicholas A. Hamilton
1Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Queensland, Australia 4072
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Richard G. Morris
2Simons Centre for the Study of Living Machines, National Centre for Biological Sciences, Tata Institute for Fundamental Research, 560065 Bangalore, India
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  • For correspondence: s.budnar@imb.uq.edu.au richardgm@ncbs.res.in
Alpha S. Yap
1Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Queensland, Australia 4072
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Abstract

Scaffolding is a fundamental principle of cell signaling commonly thought to involve multi-domain proteins that tether different components of a pathway together into a complex 1,2. We now report an alternative mechanism for scaffolding that is necessary for RhoA-mediated contractile signaling. We find that anillin binding stabilizes active, GTP-RhoA, and promotes contractility at both the epithelial zonula adherens (ZA) and the cytokinetic furrow. However, anillin does not conform to the classical picture of a multi-domain tether, since its RhoA-binding AH domain alone was sufficient to promote contractile signaling. Moreover, anillin competes with contractile effectors for a common site on RhoA, presenting the conundrum of how an inhibitory interaction can otherwise promote signaling. To explain this, we propose that inactivation of RhoA is non-Poissonian, having a rate that increases with time, unless the process is reset via transient binding to anillin. Repeated cycles of binding and un-binding therefore increase cortical residence times of non-sequestered GTP-RhoA and hence the probability of engaging contractile effectors. We identify the modification of the local lipid environment as a potential mechanism underlying such non-Poisson statistics, and demonstrate agreement with a minimal cellular system. Finally, we show that Myosin II anchors anillin at the cortex to form a feedback pathway that enhances RhoA signaling. This new paradigm of scaffolding is a regulatory analogue of kinetic proofreading and may be employed by other binding proteins that do not fit the classical picture.

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Posted March 18, 2018.
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Scaffolding of RhoA contractile signaling by anillin: a regulatory analogue of kinetic proofreading
Srikanth Budnar, Kabir B. Husain, Guillermo A. Gomez, Maedeh Naghibosidat, Suzie Verma, Nicholas A. Hamilton, Richard G. Morris, Alpha S. Yap
bioRxiv 282756; doi: https://doi.org/10.1101/282756
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Scaffolding of RhoA contractile signaling by anillin: a regulatory analogue of kinetic proofreading
Srikanth Budnar, Kabir B. Husain, Guillermo A. Gomez, Maedeh Naghibosidat, Suzie Verma, Nicholas A. Hamilton, Richard G. Morris, Alpha S. Yap
bioRxiv 282756; doi: https://doi.org/10.1101/282756

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