Synaptic Kalirin-7 and Trio Interactomes Reveal a GEF Protein-Dependent Neuroligin-1 Mechanism of Action

Jeremiah D. Paskus; Chen Tian; Erin Fingleton; Christine Shen; Xiaobing Chen; Yan Li; Samuel A. Myers; John D. Badger, II; Michael A. Bemben; Bruce E. Herring; Katherine W. Roche

Cell Reports (Dec 2019)

Synaptic Kalirin-7 and Trio Interactomes Reveal a GEF Protein-Dependent Neuroligin-1 Mechanism of Action

Jeremiah D. Paskus,
Chen Tian,
Erin Fingleton,
Christine Shen,
Xiaobing Chen,
Yan Li,
Samuel A. Myers,
John D. Badger, II,
Michael A. Bemben,
Bruce E. Herring,
Katherine W. Roche

Affiliations

Jeremiah D. Paskus: Receptor Biology Section, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD, USA; Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC, USA
Chen Tian: Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA; Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA
Erin Fingleton: Receptor Biology Section, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD, USA
Christine Shen: Laboratory of Neurobiology, NINDS, NIH, Bethesda, MD, USA
Xiaobing Chen: Laboratory of Neurobiology, NINDS, NIH, Bethesda, MD, USA
Yan Li: Protein/Peptide Sequencing Facility, NINDS, NIH, Bethesda, MD, USA
Samuel A. Myers: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
John D. Badger, II: Receptor Biology Section, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD, USA
Michael A. Bemben: Receptor Biology Section, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD, USA; Department of Biology, The Johns Hopkins University, Baltimore, MD, USA
Bruce E. Herring: Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA; Corresponding author
Katherine W. Roche: Receptor Biology Section, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD, USA; Corresponding author

Journal volume & issue: Vol. 29, no. 10
pp. 2944 – 2952.e5

Abstract

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Summary: The RhoGEFs Kalirin-7 and Trio are regulators of synaptic plasticity, and their dysregulation is associated with a range of neurodevelopmental and neurodegenerative disorders. Although studies have implicated both Kalirin and Trio in certain diseases, such as tauopathies, they remarkably differ in their association with other disorders. Using unbiased proteomics, we identified interactomes of Kalirin-7 and Trio to ascertain distinct protein association networks associated with their respective function and revealed groups of proteins that preferentially interact with a particular RhoGEF. In comparison, we find Trio interacts with a range of axon guidance and presynaptic complexes, whereas Kalirin-7 associates with several synaptic adhesion molecules. Specifically, we show Kalirin-7 is an interactor of the cell adhesion molecule neuroligin-1 (NLGN1), and NLGN1-dependent synaptic function is mediated through Kalirin-7 in an interaction-dependent manner. Our data reveal not only the interactomes of two important disease-related proteins, but also provide an intracellular effector of NLGN1 function. : Paskus et al. use quantitative proteomics to determine the synaptic interactomes of the disease-associated proteins Kalirin-7 and Trio, identifying Kalirin-7 as an interactor of NLGN1. Investigation of this interaction unveils Kalirin-7 as a primary intracellular effector of NLGN1 gain of function. Keywords: neuroligin, kalirin, Trio, synaptic transmission, synaptogenesis, proteomics

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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