Lymphoma Mutations Seen to Open Four ‘Locks’ on Key Protein to Promote Cancer

Lymphoma Mutations Seen to Open Four ‘Locks’ on Key Protein to Promote Cancer

Researchers at Johns Hopkins have discovered that mutations in lymphoma cells allow these cells to break through four different locks on the protein CARD11, putting the protein in a constantly activated state and contributing to cancer development.

The team, led by Joel Pomerantz, published their findings in two articles in the Journal of Biological Chemistry; “Intramolecular Interactions and Regulation of Cofactor Binding by the Four Repressive Elements in the Caspase Recruitment Domain-Containing Protein 11 (CARD11) Inhibitory Domain”  and “Cooperative Control of Caspase Recruitment Domain-Containing Protein 11 (CARD11) Signaling by an Unusual Array of Redundant Repressive Elements.”

“A lot of the immune system’s signaling proteins have a lock built into them to prevent miscommunication with other proteins,” Dr. Pomerantz, an associate professor of biological chemistry at the Johns Hopkins University School of Medicine, said in a press release. “This is the first one we know of that has four locks.”

The research team first started investigating the protein years ago, following reports that some 10 percent of all patients with the activated B cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) have mutations in CARD11. They then discovered that the protein had four different molecular locks — mechanisms making sure the factor is only activated when needed.

“Surprisingly, none of the mutations exist in the lock region of CARD11, and we wanted to know why,” Dr. Pomerantz said.

CARD11, part of the body’s immune defense, is activated only when it encounters parts of invading pathogens that are displayed by other immune cells to alert the system to an infection. When CARD11 becomes active, it signals immune B- and T-cells to multiply.

The team first deleted the whole region of the gene encoding the protein holding the ‘lock.’ They then methodically deleted small parts of the region, one by one. None of these deletions activated the protein, so the researchers took on the reverse approach: they deleted the whole region again and then added small bits at a time. At that point, they realized the protein has four locks and that all need to be opened for it to become active.

“Having four redundant repressive elements seems to explain why patients with lymphoma don’t have mutations in CARD11’s autoinhibitory domain,” Dr. Pomerantz said. “A mutation in any one of the repressive elements would only unlock one of the four locks, keeping CARD11’s signaling under the control of the other three.”

Mutations in the lymphoma patients are instead located in other regions of the protein. Studying CARD11 in cultured T-cells in the lab, the team found such mutations in three regions normally clasping the autoinhibitory region holding the locks. When these regions clutch the locks, the protein cannot be activated. The same regions are also engaging in interactions with other proteins once CARD11 is active. Researchers found that single mutations in these regions were enough to open all four locks.

“If we can understand how CARD11 is normally kept off, we might be able to mimic that with a drug. We also hope to shed light on how different mutations in CARD11 affect its function and a patient’s prognosis,” Dr. Pomerantz concluded.

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