John Janetzko, Ph.D.

Beckman Center B161

279 Campus Drive

Stanford, CA, 94305

Hi, I’m a basic science instructor in the Department of Molecular & Cellular Physiology at Stanford University. I work in the lab of Dr. Brian Kobilka where I use biochemical and biophysical methods to study how G protein-coupled receptors function, and specifically how they are desensitized and regulated in cells. I first joined Dr. Kobilka’s lab as a postdoctoral scholar in September 2017; my research has been supported by a Stanford School of Medicine Dean’s Postdoctoral Fellowship, a Damon Runyon Cancer Research Foundation Fellowship and most recently, a K99/R00 Pathway to Independence Award from the National Institute of General Medical Sciences (NIGMS). As a K99 fellow I am co-mentored by Dr. Mark von Zastrow at the University of California San Francisco, an expert in GPCR cell biology and trafficking. In December 2022 I was appointed as an instructor in Molecular & Cellular Physiology.

Outside the lab, I am deeply involved with the local cycling community. I train and race competitvely with Alto Velo on the Northern California/Nevada cycling scene. Outside of my own racing, I am passionate about rider education and development. I have been a coach for the Stanford University cycling teamsince 2020, leading skills clinics and teaching riders about training, nutrition and racing. I was elected to serve on the Alto Velo Board of Directors in 2022, and recently re-elected for 2023. You can follow some of my adventures on two wheels on Instagram.

news

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selected publications

Structure of the neurotensin receptor 1 in complex with β-arrestin 1

Weijiao Huang*, Matthieu Masureel*, Qianhui Qu*, John Janetzko*, Asuka Inoue, Hideaki E Kato, Michael J Robertson, Khanh C Nguyen, Jeffrey S Glenn, Georgios Skiniotis‡, and Brian K Kobilka‡

Nature, 2020

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Arrestin proteins bind to active, phosphorylated G-protein-coupled receptors (GPCRs), thereby preventing G-protein coupling, triggering receptor internalization and affecting various downstream signalling pathways (refs 1,2). Although there is a wealth of structural information detailing the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-electron microscopy structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human β-arrestin 1 (βarr1(ΔCT)). We find that phosphorylation of NTSR1 is critical for the formation of a stable complex with βarr1(ΔCT), and identify phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, we observe a phosphatidylinositol-4,5-bisphosphate molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared with a structure of a rhodopsin–arrestin-1 complex, in our structure arrestin is rotated by approximately 85° relative to the receptor. These findings highlight both conserved aspects and plasticity among arrestin–receptor interactions.
Membrane phosphoinositides regulate GPCR-β-arrestin complex assembly and dynamics

John Janetzko, Ryoji Kise, Benjamin Barsi-Rhyne, Dirk H Siepe, Franziska M Heydenreich, Kouki Kawakami, Matthieu Masureel, Shoji Maeda, K Christopher Garcia, Mark Zastrow, Asuka Inoue‡, and Brian K Kobilka‡

Cell, 2022

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Binding of arrestin to phosphorylated G protein-coupled receptors (GPCRs) is crucial for modulating signaling. Once internalized, some GPCRs remain complexed with β-arrestins, while others interact only transiently; this difference affects GPCR signaling and recycling. Cell-based and in vitro biophysical assays reveal the role of membrane phosphoinositides (PIPs) in β-arrestin recruitment and GPCR-β-arrestin complex dynamics. We find that GPCRs broadly stratify into two groups, one that requires PIP binding for β-arrestin recruitment and one that does not. Plasma membrane PIPs potentiate an active conformation of β-arrestin and stabilize GPCR-β-arrestin complexes by promoting a fully engaged state of the complex. As allosteric modulators of GPCR-β-arrestin complex dynamics, membrane PIPs allow for additional conformational diversity beyond that imposed by GPCR phosphorylation alone. For GPCRs that require membrane PIP binding for β-arrestin recruitment, this provides a mechanism for β-arrestin release upon translocation of the GPCR to endosomes, allowing for its rapid recycling.