How shape-shifting receptors affect cell growth

CAMBRIDGE, MA – Receptors found on the surface of cells bind to hormones, proteins, and other molecules, helping cells respond to their environment. MIT chemists have now discovered how one of these receptors changes its shape when it binds to its target, and how that change triggers cells to grow and reproduce.

This receptor, known as the epidermal growth factor receptor (EGFR), is overexpressed in many cancers and is the target of several cancer drugs. These drugs often work well at first, but tumors can become resistant to them. Better understanding the mechanism of these receptors could help researchers design drugs that can circumvent that resistance, said Gabriela Schlau-Cohen, a professor of chemistry at MIT.

“Thinking about more general mechanisms for targeting EGFR is an exciting new direction, and gives you new avenues for thinking about possible therapies that may not develop resistance easily,” he said.

Schlau-Cohen and Bin Zhang, Pfizer-Laubach Assistant Professor of Career Development Chemistry, are senior authors of the study, which appears today in Nature Communications. The paper’s lead authors are MIT graduate student Shwetha Srinivasan and former MIT postdoc Raju Regmi.

Shape-shifting receptors

The EGF receptor is one of many receptors that help control cell growth. Found in most types of mammalian epithelial cells, which line body surfaces and organs, can respond to several types of growth factors other than EGF. Some types of cancer, especially lung cancer and glioblastoma, overexpress EGF receptors, which can lead to uncontrolled growth.

Like most cell receptors, EGFR spans the cell membrane. The extracellular region of the receptor interacts with its target molecule (also called a ligand); the transmembrane portion is embedded within the membrane; and the intracellular portion interacts with the cellular machinery that controls the growth pathway.

The extracellular portion of the receptor has been analyzed in detail, but the transmembrane and intracellular portions are difficult to study because they are more irregular and cannot be crystallized.

About five years ago, Schlau-Cohen tried to learn more about the little-known structure. His team embedded the protein in a special type of self-assembly membrane called a nanodisc, which mimics a cell membrane. Then, he used a single molecule FRET (fluorescence resonance energy transfer) to study how the receptor’s conformation changes when it binds to EGF.

FRET is usually used to measure the small distance between two fluorescent molecules. The researchers labeled the nanodisc membrane and the protein’s intracellular tail end with two different fluorophores, which allowed them to measure the distance between the protein tail and the cell membrane, under various circumstances.

Surprisingly, the researchers found that binding of EGF causes a large change in the conformation of the receptor. Most models of receptor signaling involve the interaction of multiple transmembrane helices to bring about large-scale conformational changes, but the EGF receptor, having only a single helix segment within the membrane, appears to undergo such changes without interacting with other receptor molecules.

“The idea of ​​a single alpha helix capable of transducing such a large conformational rearrangement really surprised us,” said Schlau-Cohen.

Molecular modeling

To learn more about how this shapeshifting will affect receptor function, the Schlau-Cohen lab teamed up with Zhang, whose lab performs computer simulations of molecular interactions. This kind of modeling, known as molecular dynamics, can model how molecular systems change over time.

Modeling shows that when the receptor binds to EGF, the extracellular segment of the receptor stands vertically, and when the receptor is unbound, lies flush with the cell membrane. Similar to hinge closure, when the receptor falls flat, it tilts the transmembrane segment and pulls the intracellular segment closer to the membrane. This blocks the intracellular regions of the protein from interacting with the machinery needed to launch cell growth. EGF binding makes the region more available, helping to activate growth signaling pathways.

The researchers also used their model to find that positively charged amino acids in the intracellular segment, near the cell membrane, are key to this interaction. When the researchers mutated the amino acid, switching it from charged to neutral, ligand binding no longer activated the receptor.

“There is a good consistency we can see between simulation and experiment,” Zhang said. “With molecular dynamics simulations, we can find out which amino acids are important for coupling, and measure the role of different amino acids. Then Gabriela showed that the prediction turned out to be true.”

The researchers also found that cetuximab, a drug that binds to the EGF receptor, prevents this conformational change from occurring. Cetuximab has shown some success in treating patients with colorectal or head and neck cancer, but tumors can become resistant to it. Learning more about the mechanisms by which EGFR responds to different ligands could help researchers design drugs that are less likely to cause resistance, the researchers said.

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