Open Postdoctoral position, faculty mentor Ruth Huttenhain

The Hüttenhain Lab at Stanford University is seeking a postdoctoral fellow to investigate how G protein-coupled receptors (GPCRs) engage non-canonical intracellular effectors through intrinsically disordered regions (IDRs). The project integrates mass spectrometry-based proteomics, structural biology, and molecular biology to define new modes of GPCR signaling. We are particularly interested in candidates with strong backgrounds in proteomics and/or structural biology and/or computational structural biology, ideally complemented by molecular biology expertise, who are excited to work at the interface of these disciplines.

Lab overview: The Huttenhain lab in the Molecular & Cellular Physiology Department at Stanford University studies how intracellular signaling networks are organized and remodeled downstream of GPCRs, the largest family of membrane receptors, which mediate most physiological responses to hormones, neurotransmitters, and environmental stimulants. We take an interdisciplinary approach that combines proximity labeling proteomics, structural biology, computational modeling, and functional cell biology to understand how signaling network dynamics translate extracellular cues into specific phenotypic outputs.

Project specifics: Although GPCRs bind an enormous diversity of ligands and produce a wide range of physiological outcomes, they are thought to signal through just two effector families: heterotrimeric G proteins and β-arrestins. This canonical signaling paradigm cannot fully explain how each GPCR encodes its own unique biological output. Our lab and others have recently shown that GPCRs also engage non-canonical effectors through intrinsically disordered regions (IDRs) in their intracellular loops and C-terminal tails, regions that are largely absent from experimentally resolved structures and have therefore remained understudied. 

Building on these findings, the postdoc will join an interdisciplinary team spanning proteomics, structural biology, and molecular biology, working together to identify, structurally characterize, and functionally dissect protein interactions with GPCR IDRs across the broader GPCR superfamily. Within this collaborative framework, the postdoc will have the intellectual freedom and support to shape their own research direction leveraging the following interconnected approaches:

1. Systematically mapping GPCR-IDR interactomes across a prioritized panel of GPCRs using APEX-based proximity labeling proteomics.
2. Structural characterization of GPCR-IDR-protein complexes using structural proteomics approaches (cross-linking MS, HDX-MS), AlphaFold-based structural prediction, cryo-EM (through collaborations), and targeted mutagenesis with biochemical validation.
3. Determining the functional consequences of GPCR-IDR interactions on receptor signaling, trafficking, and organelle biology using cellular assays, functional genomics (CRISPR), and quantitative imaging.

Relevant publications:

• Lobingier BT, Hüttenhain R, Eichel K, Ting AY, Miller KB, von Zastrow M, Krogan NJ. An approach to spatiotemporally resolve protein interaction networks in living cells. Cell 169, 350–360 (2017). PMC5616215.
• Polacco BJ, Lobingier BT, Blythe EE, Abreu N, Xu J, Li Q, Naing ZZC, Shoichet BK, Levitz J, Krogan NJ, von Zastrow M, Hüttenhain R. Profiling the diversity of agonist-selective effects on the proximal proteome environment of G protein-coupled receptors. bioRxiv 2022.03.28.486115.
• Zhong X, Li Q, Polacco BJ, Patil T, DiBerto JF, Vartak R, Xu J, Marley A, Foussard H, Roth BL, Eckhardt M, von Zastrow M, Krogan NJ, Hüttenhain R. An automated proximity proteomics pipeline for subcellular proteome and protein interaction mapping. bioRxiv 2023.04.11.536358.

Academic environment: Stanford University provides a highly stimulating scientific environment that fosters collaborations and the exchange of ideas within and across disciplines. The Molecular & Cellular Physiology Department (https://med.stanford.edu/mcp.html) offers a world-class scientific environment and supports postdoctoral scholars throughout their postdoc with mentoring and training programs, seminar series, and annual retreats. The Hüttenhain Lab is committed to cultivating an inclusive, respectful, and collaborative environment with a shared passion for science and mentorship. The postdoc will have the opportunity to mentor graduate and undergraduate trainees. The postdoc will also have access to outstanding infrastructure and resources, including dedicated, state-of-the-art mass spectrometers, cryo-EM facilities, high-performance computing, and Stanford's broader ecosystem of core facilities.