From protein mechanisms to targeted therapeutics

How are nutrients recognized by their protein sensors? How is their transport across cellular and intracellular membranes regulated? And, how is nutrient sensing integrated with other chemical signals, such as hormones, to determine cellular decisions, especially the decision: to grow or not to grow?

We are a team of highly driven and dedicated scientists, working at the interface of biology and chemistry to answer these fundamental questions at the level of atoms and single molecules. We use a full range of approaches from structural biology, chemical biology, cell biology, biophysics, and biochemistry — to discover new basic knowledge, and contribute to the development of therapeutics for devastating diseases of growth, including cancer and tuberous sclerosis.

Our lab is an integral part of the Stanford Cancer Institute, the Department of Structural Biology, and the Department of Chemical and Systems Biology.

We are always on the lookout for new Post-docs and PhD students — if you share our passion and commitment to fight cancer, please get in touch!

News

GATOR2 structure render

July 13, 2022

GATOR2 mysterious no more [Nature]

Our lab has just made a huge dent in one of the most elusive problems of the nutrient sensing field — and that is the mechanism of how GATOR2 works on the molecular level. This was a collaborative project with Max Valenstein.

GATOR2 is a protein complex composed of five individual subunits which have been shown to work together to (1) receive signals from individual nutrient sensors that detect cellular levels of amino-acids leucine, arginine, and (2) to relay that information to mTORC1 machinery, to make informed metabolic decisions for the cell.

Full disclosure — we have not figured out how GATOR2 works just yet. But we made the first step towards that goal. Below is a short summary of what we found, and what’s now been published in Nature [paywall-free link].

Many congratulations to the whole team!

  • We have determined a 3.7 Å cryo-EM structure of GATOR2, and built its atomic model.
  • GATOR2 looks like a drone, with the central octagonal scaffold surrounded by multiple WD40 β-propellers. In fact, a single GATOR2 particle has sixteen β-propellers!
  • The octagonal scaffold is assembled thanks to a set of two distinct protein-protein interactions:
    • α-solenoid — α-soleonoid junctions.
    • CTD—CTD junctions, which involve zinc-coordinating RING and zinc-finger domains.
  • The CTD junctions constitute a structurally novel protein dimer, which has not been observed before. In fact, the presence of RING domains in GATOR2 initially fooled us into thinking that this complex must have an enzymatic function — similarly to RING domains involved in ubiquitin transfer. However, as we found out in this study, GATOR2 does not seem to transfer ubiquitin at any conditions tested, and neither is ubiquitylation required for passing the signal from GATOR2 to mTORC1. Instead, we discovered that the role of RING domains in GATOR2 is to assemble the GATOR2 octagon, which acts as a scaffold for signal transduction activities.
  • The octagonal scaffold is supported by a number of extra β-propellers which rigidify the α-solenoid and CTD junctions.
  • And most excitingly, there are three distinct sets of β-propellers that emanate from the scaffold and point outwards — which we found are critical for:
    • Receiving signal from the leucine sensor Sestrin2
    • Receiving signal from the arginine sensor CASTOR1
    • Relaying these signals to mTORC1 (via GATOR1)

Our work continues.

Stay tuned for new discoveries coming from our lab. And please consider joining us (as a Post-doc or a PhD student) — to help us figure out how GATOR2 works!

June 12, 2022

Kacper presents at the Small GTPase conference

Kacper was invited to present our team’s efforts on deciphering how Rag GTPases work — at the FASEB conference Regulation and Function of Small GTPases in Vermont Academy [Saxtons River, Vermont]. It was the first time that Rags were featured at this famous conference, which is celebrating 30 years in the running.

Kacper was also involved in a career workshop with current trainees — by sharing the experience of applying to faculty positions and setting up a lab.

Thank you, Anne Ridley and Mark Philips for organizing a fantastic meeting. It was a humbling experience to meet so many giants in the field and to learn about the terrific research coming out from many labs around the globe. Lots of new ideas and potential collaborations!

Cannot wait for the next meeting in 2024!

June 8, 2022

INFORS shakers are here!

Kacper is unable to contain himself — our workhorse shakers have just arrived. Thank you to Eddie Nazzal and the INFORS team for making this happen in a timely manner.

These shakers are absolute beasts — we use them to grow tens of liters of bacteria, yeast, and insect cells. It’s time to put the shaker platforms and the racks together! We are going to need loads of flasks.

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RESEARCH

Metabolic growth control

Our mission is to elucidate how cells make growth decisions — to grow or not to grow — based on their environmental conditions, such as availability of nutrients or growth factors. We synthesize proteins responsible for these decision-making processes, and we determine what these proteins look like in three dimensions and how they function.

It turns out that many of these growth decision-making proteins interact with the surface of the lysosome, which beyond its nutrient-recycling function, also works as a sophisticated signaling center, able to sense the availability of nutrients and direct cellular metabolism. Working together, these proteins are able to adjust biological metabolism by switching between anabolism (growth) and catabolism (recycling) — in response to the environment, and in the matter of minutes. Collectively, we call these proteins “the mTOR pathway”, because the major enforcer of these decisions is a protein kinase called mTOR.

mTOR is supported by Raptor and mLST8 in assembling mTOR complex 1 (mTORC1), which docks and gets activated on the lysosomal surface via association with two GTPases: Rag and Rheb. These GTPases are sensitive to nutrients and growth factors and constitute the molecular AND logic gate for cellular growth.

Our lab is deciphering how this decision-making system works.

RESEARCH

Nutrient trafficking

We are fascinated by how nutrients are trafficked inside cells — by membrane protein transporters, and how that trafficking is hijacked and exploited to fuel cancer growth. For example, many oncogene-transformed pancreatic cancers often elude even the harshest chemotherapy treatments, because they can survive in nutrient-poor environments while other cells cannot. These cancer cells rewire their metabolism into macrophage-style consumers of extracellular protein. Instead of relying on standard nutrient uptake of metabolites, these cancer cells scavenge and recycle protein (via macropinocytosis and autophagy), digest it inside lysosomes, and then release it as amino acids to fuel their growth. It turns out that the release of digested amino acids from the lysosome to cytosol is fully controlled by nutrient transporters, and our lab is developing novel therapies that specifically target cancer cells based on their unorthodox eating habits.

Beyond their canonical function of ferrying nutrients, these transporters also serve as receptors and regulators to actively fine-tune the cellular responses to fluctuating nutrient levels. With structural and chemical biology tools, our lab is spearheading efforts towards revealing how these transceptors (transporters + receptors) work and how they communicate with the growth machinery of the cell.

At all stages of our work, we develop binders — and by binders we mean small molecules or biologics (antibodies / nanobodies) that interact with a target protein. Such interactions often result in either inhibition or augmentation of cellular function of these proteins. And we use these binders as research tools, and also as starting points for the development of novel cancer therapeutics — in collaborations with chemists, computational biologists, bioengineers and clinicians.

People

Kacper Rogala

Assistant Professor

Dr. Kacper Rogala is an Assistant Professor at Stanford University School of Medicine with a joint appointment between the Department of Structural Biology and the Department of Chemical and Systems Biology. He is also a Leader in the Stanford Cancer Institute.

BSc(Hons): University of Edinburgh, Scotland
MRes: University College London, England
DPhil: University of Oxford, England
Postdoctoral Fellow: Massachusetts Institute of Technology, USA

Kacper was born and raised in Poland, and educated in three wonderful British cities: Oxford, London and Edinburgh, where he studied chemistry of living things, or simply — biochemistry. During his studies, Kacper developed a deep passion for proteins — how they work, what they look like, and how they interact with other proteins and small molecules. This passion led him to pursue a trans-Atlantic postdoc between two Cambridges: one in the UK and one in Massachusetts. As a researcher at MIT, the Whitehead Institute, the Broad Institute, and the MRC Laboratory of Molecular Biology, Kacper began unraveling the mechanisms of nutrient sensing on the surface of lysosomes.

Kacper joined Stanford as an assistant professor in 2022, and together with his team they are leading the charge towards mechanistic understanding of how cells control metabolism in response to nutrients and growth factors, and ways to modulate these activities with chemical probes — for the benefit of patients.

You can listen to an interview with Kacper by the Tuberous Sclerosis Association.

And here is another short interview with Kacper — from his time at MIT.

Kacper has earned numerous awards for his work, including: • The NIH Pathway to Independence Award from the National Cancer Institute • Margaret and Herman Sokol Postdoctoral Award in Biomedical Research from the Whitehead Institute • Postdoctoral Research Fellowship Award from the Charles A. King Trust • Junior Research Fellowship from the Tuberous Sclerosis Association • Best Master of Research Student Prize from University College London for the top graduating student.

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Dominic Eberle

Graduate Student

Dominic Eberle, originally Filipino and Swiss, grew up moving around Southeast Asia. He settled down in the Netherlands for his undergraduate studies at Maastricht University. After obtaining a BSc in Biomedical Sciences, he moved north to continue his education in Amsterdam and to pursue his scientific interest in cancer biology.

Dominic is currently working on his MSc thesis in the Rogala Lab, studying the mechanisms of nutrient trafficking in cells.

BSc: Maastricht University, The Netherlands

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Beatriz Castro

Graduate Student

Beatriz Castro is originally from a sunny fishing town in Portugal known for its massive waves. While in Portugal, she attended the University of Aveiro and obtained her undergraduate degree in Biochemistry. As she had always dreamed of going abroad and experiencing different teaching approaches, after completing her Bachelor’s degree, she moved to Finland to start a Master’s degree in Genetics and Molecular Biosciences.

Initially, Beatriz had the idea to stay away from proteins, and to broaden her knowledge of genetics instead — only to soon find herself in the US doing her Master’s thesis in structural biology in the Rogala Lab. While she loves exploring new countries and cultures, she deeply misses her two cats back at home who she can’t stop talking about and showing pictures of.

BSc: The University of Aveiro, Portugal

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Karen Linde-Garelli

Research Assistant

Karen Linde-Garelli was born in Argentina and grew up in Texas. She completed her undergraduate studies in biomedical engineering at Rochester Institute of Technology, during which time she also worked at Regeneron, ATCC, and Relay Therapeutics as part of a cooperation education program.

Throughout her time at RIT, Karen had the opportunity to explore different facets of research involved in targeted therapies for cancer and high-profile diseases. In this time, she contributed to enabling a fully-automated robotics platform for R&D testing, as well as creating & characterizing new tools for studying the function & regulation of proteins in cancer, diabetes, and macular degeneration. Then, after receiving her bachelor’s degree, she began working in the Rogala Lab, studying structure-function mechanisms of protein-protein interactions that affect cell growth, metabolism, and disease.

BSc: Rochester Institute of Technology, New York, USA

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FEATURED PUBLICATIONS

blue & bold — Rogala Lab member
Ψ — equal contribution
@ — corresponding author

Structure of the nutrient-sensing hub GATOR2

Max L ValensteinΨ@, Kacper B RogalaΨ@, Pranav V. Lalgudi, Edward J Brignole, Xin Gu, Robert A Saxton, Lynne Chantranupong, Jonas Kolibius, Jan-Philipp Quast, David M Sabatini.

Nature. 607(7919):610-616. 2022 July 13.

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Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex.

Kuang ShenΨ, Kacper B RogalaΨ, Hui-Ting Chou, Rick K Huang, Zhiheng Yu, David M Sabatini

Cell. 179(6):1319-1329.e8. 2019 November 27.

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Structural basis for the docking of mTORC1 on the lysosomal surface.

Kacper B Rogala, Xin Gu, Jibril F Kedir, Monther Abu-Remaileh, Laura F Bianchi, Alexia M S Bottino, Rikke Dueholm, Anna Niehaus, Daan Overwijn, Ange-Célia Priso Fils, Sherry X Zhou, Daniel Leary, Nouf N Laqtom, Edward J Brignole, David M Sabatini.

Science. 366(6464):468-475. 2019 October 25.

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Join the Rogala Lab

Our lab is friendly to trainees from all walks of life, and we cherish trust, inclusiveness and intellectual curiosity, where no question is too big to study, as long as we have the right approach and a unique angle. Most importantly, our lab operates with a growth mindset for all of our trainees, and we put a heavy emphasis on training and skills development — across a wide range of experimental and computational techniques. And through collaboration, strong work ethic, seeking feedback, and trying out new strategies, we drive innovation and novel discoveries for our team.

If this is something you might be interested in, please contact Kacper directly. We are always on the look out for driven individuals to join our lab! Even if we do not have an open position currently advertised, please message us if you think you can fit into our team.

Please write a few lines about yourself — about your previous research experience, and what you liked about our lab that made you email us! We will be very happy to tell you more about potential projects, our style of doing research, and importantly — how this lab can be an opportunity for you to become even better scientifically, and how in this lab, the translational nature of our work can make an impact in patients’ lives — by cracking challenging basic science questions and developing novel therapeutics.

We have an official post-doc opening in the lab! Please see here for details.

We are looking for highly driven candidates with expertise in either structural biology, chemical biology, biochemistry, bioengineering, or cell biology. Please provide your CV, cover letter (see the ad for details), and contact information to three reference writers. We set the compensation of our postdocs to the Stanford rates, and we strongly encourage the candidates to explore applying for extramural fellowships and grants to support their research.

Among the many fellowships and funding opportunities available to postdocs at Stanford (see a comprehensive list here), you might also be eligible for a number of programs specifically focused on postdocs from underrepresented backgrounds — please see the list here.

General Information about postdoctoral fellowships at Stanford may be found at the Stanford Postdoctoral Scholars site.

We are accepting graduate students from all Stanford science and engineering programs (PhD, MD/PhD). First year students who are interested in joining our lab please message Kacper directly, attach your CV, and say a few words about yourself.

In general, our lab is most suitable to highly motivated graduate students with keen interest in protein chemistry, structural biology, chemical biology and drug discovery. If you are thrilled by the prospect of discovering fundamental biological mechanisms and applying that knowledge in our shared quest to fight cancer, then this lab is for you.

Please note that at Stanford, prospective PhD and MD/PhD students apply to graduate programs (for example Stanford Biosciences Home Programs), and only through those programs they join individual labs, including ours. Prior to joining their thesis lab, PhD students rotate in 3 different labs (on average) to find the topic and the environment that works best for them.

Exchange PhD students (American and international) — we will be happy to host you for a part of your PhD thesis in our lab — to work in collaboration with us on a specific project. If you are studying cell growth / nutrient sensing / nutrient trafficking, please get in touch with Kacper and get the conversation started. Primary requirement: you will need to be fully enrolled in a PhD program at your home university.

We are accepting Master’s students currently enrolled in American and international universities — for their thesis research project. We expect from you a minimum of an 8-months commitment towards your project.

We welcome students from a broad range of science and engineering backgrounds — including biochemistry, cell biology, molecular biology, biophysics, biotechnology, bioengineering, chemistry, chemical engineering, pharmacology, bioinformatics, or similar.

Please email Kacper directly, and provide your CV and contact information to one reference writer.

We are accepting Stanford undegraduate students to join our lab.

We are looking for dedicated students whose goal is to pursue a PhD in the future. We are specifically looking for students who want to commit to our lab for the entire duration of their college career. During term-time, you will be working part-time with your mentor (either a postdoctoral fellow or a PhD student), and during summer, you will work full-time and be responsible for your own unique research project.

Interested undegraduate students, please email Kacper directly.

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