Two new studies led by Yale elucidate protein structure and function in ALK, a protein receptor, which may contribute to new treatments for pediatric neuroblastoma and lymphoma.
Two new studies led by Yale and published in Nature on Nov. 24 have revealed further details about the anaplastic lymphoma kinase molecule, or ALK, and its role in cancer formation.
After years of research to try to find out more about ALK, these two studies made progress in determining its structural status as a receptor protein. Daryl Klein, assistant professor of pharmacology at the Yale School of Medicine, is a senior author of one of the studies, meanwhile, Joseph Schlessinger, professor of pharmacology and co-director of the Institute of Cancer Biology, is the main author of the other.
“[ALK] is one of the receptor tyrosine kinases whose aberrant activation causes carcinogenesis, ”wrote Tongqing Li, postdoctoral associate at Klein’s Lab. “Physiologically, binding to the ligand [the specific signal] triggers the activation of ALK. But how this happens is unknown. Our structures show how ligand binding drives two receptors together.
ALK, like other receptors, works to receive signals from other parts of the body to synthesize new proteins or perform other actions. Activation of the receptor depends on ligand binding and dimerization, the process by which receptors are internalized into cells and complete the necessary action.
ALK receptors are usually located in the brain and central nervous system, and they are activated by binding ligands. Although it is still not known which ligands specifically bind to it, the internalization of the receptor into the cell, or dimerization, has been implicated in the growth and development of cancer; In addition, as a tyrosine kinase, ALK serves as an on / off switch for cellular functions.
“The ALK receptor tyrosine kinase was originally discovered as an oncogenic fusion protein,” Schlessinger wrote in an email to the News. “At least 20 distinct partners of oncogenic ALK fusion proteins generated by chromosomal translocations have been found to be the primary drivers of a variety of cancers, including large B-cell lymphomas and inflammatory myofibroblastic tumors. ALK oncogenic mutants have also been identified in pediatric neuroblastoma.
Dimerization of the ALK receptor has been linked to the development of these cancers, and it can occur through mutations in cells of nervous tissue. Additionally, chromosomal translocation, or the exchange of chromosomal parts, can also stimulate ALK tyrosine kinase activity and lead to these cancers.
Findings concerning the structure of ALK receptors may explain the mechanism of activation of receptor tyrosine kinases. By understanding the mechanisms, pharmaceutical companies can adopt new drugs that inhibit ALKs to prevent activation of these receptors and provide treatment for some cancers. These treatments could be applied to diseases like neuroblastoma, one of the most common pediatric cancers accounting for about 12 percent of childhood cancer mortality, according to Klein.
“The protein that we observed during our experiments revealed a surprising architecture,” Klein wrote in an email to News. “It can be broken down into 3 regions. A handle, a rigid pole-shaped extension and a sensor. The rigid polar region that we have called the “pole” because of its rod-like appearance, and pole is short for Polyglycine Extension. The sensor region, or PXL (Polyglycine eXtension Loops), is what “captures” a second ALK protein. And when 2 ALKs come together in this way, it activates the receiver to signal.
Due to the discovery of this receptor structure and mechanism, ALK inhibitors are intended to target and bind to the region of the ALK sensor in order to prevent its activation and cancer growth signals. However, since cancers are constantly evolving and mutating, the inhibitory mechanism itself cannot be a permanent treatment.
Research is being carried out in the hope of finding a combination of the inhibitory mechanism and antibodies that would be able to effectively deactivate the ALK activation complex. This would circumvent the deficiencies of chemical inhibitor therapy and apply the structural findings to potent therapy using the strength of antibodies.
“In some ways, cancer can be seen to have the same challenges as SARS COV-2,” Klein wrote to the News. “Just like we use antibodies and small molecules to beat Covid, we now have a new model for ALK to beat neuroblastoma. We can use the same analogy to understand oncogenic mutations in ALK. This is an area of ongoing research for us. Any mutation in this uniquely folded glycine-rich polar region will certainly cause misfolding or flexing that cannot be extinguished. So we are trying to find ways to “fix” the problem, in cases where such mutations are associated with cancer. ”
The lab work was conducted at Yale School of Medicine in the Klein and Schlessinger labs, with contributions from the Department of Structural Biology at St. Jude Children’s Research Hospital.
Manas sharma | [email protected]