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
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
