By Jon Atherton
An interdisciplinary team of Yale scientists are coming together to address crucial questions about how the cell membrane environment affects membrane proteins, with support from The National Institute of General Medical Sciences (NIGMS).
The team of seven researchers from the Yale School of Medicine’s Departments of Pharmacology and Cell Biology, and the Yale Cancer Biology and Nanobiology Institutes will receive $10.5 million to explore the native lipids in which membrane proteins are embedded and define the role of this environment on the functions and structure of these proteins.
Cell membranes serve as barriers and gatekeepers that regulate the transport of information and materials in and out of the cell, but also provide a special environment for a large class of proteins that regulate processes that help cells communicate and survive.
Proteins within cell membranes account for around one-third of all human proteins and are the target for over 60% of current drugs. Scientists are particularly interested in the structure and function of such proteins to shed light on their role in disease progression and in the development of new therapeutics.
However, researchers traditionally have had to remove proteins from the cell membrane in order to study them, thus losing valuable information about the membrane context.
“Studying membrane proteins in the absence of a membrane is like looking at only part of a picture,” said principal investigator Kathryn Ferguson, Associate Professor of Pharmacology at the Yale Cancer Biology Institute.
“We are developing new ways to study membrane proteins in their natural environments, so we can see how proteins and other membrane components work together to carry out their unique biological functions.”
Recent advances in mass spectrometry, cryo-electron microscopy, and optical imaging – all strengths of the Yale team and supported by research technology at Yale’s West Campus and the Yale School of Medicine – provide an exciting opportunity to understand membrane proteins in their native states.
Supported through the NIGMS’ team science RM1 program, the research program combines the complementary expertise of multiple investigators to achieve outcomes that are typically beyond the efforts of individual laboratories.
“Our team members bring a wealth of expertise to the project with skills in cryo electron microscopy, top-down and bottom-up mass spectrometry, multi-omic analysis, optical imaging, biochemistry, protein dynamics, and cellular signaling,” said Dr. Ferguson.
The goal of the collaborative team is to develop new technologies and approaches that will define the lipid and protein components of functional complexes, evaluate the role of the local membrane environment in function and regulation of integral proteins, and determine the structures of these assemblies.
In addition to Ferguson, primary investigators of the program will be:
- Joel Butterwick, Assistant Professor of Pharmacology
- Kallol Gupta, Assistant Professor of Cell Biology, Yale Nanobiology Institute
- Daryl Klein, Associate Professor of Pharmacology, Yale Cancer Biology Institute
- Yansheng Liu, Associate Professor of Pharmacology, Yale Cancer Biology Institute
- Wei Mi, Assistant Professor of Pharmacology
- Joseph Schlessinger, William H. Prusoff Professor of Pharmacology, Yale Cancer Biology Institute
Moitrayee Bhattacharyya (Assistant Professor of Pharmacology), and Mark Lemmon (Chair of Pharmacology and co-Director of the Cancer Biology Institute) are also key contributors to the project.
The research, which is funded through the NIGMS Collaborative Program Grant for Multidisciplinary Teams (RM1), will receive funding for five years. The Yale team also received prior support from the Yale School of Medicine Program for the Promotion of Interdisciplinary Team Science (POINTS) to foster the initial collaboration among the investigators.