Key Findings: Mayo Clinic researchers have determined the molecular structures of protein kinase C beta (PKCβ), a family of proteins involved in cell signaling and implicated in cancer and neurological diseases. The study was published in Nature Communications.
Structure Determination
For the first time, the full-length human PKCβ1 and PKCβ2 structures were resolved. The team produced human PKC enzymes in human cells rather than insect cells, yielding high-quality material that enabled structural analysis.
Activation Mechanism
The structures revealed that PKCβ transitions from a closed, inactive state to an open, membrane-bound active state upon binding to lipid membranes. The lipids act as a molecular lever, exposing the active site.
Drug Mechanism
Endoxifen, a breast cancer drug, inhibits PKCβ through an allosteric mechanism. It stabilizes the protein at cellular membranes, leading to its degradation. This differs from previous PKC inhibitors that targeted the active site directly.
Implications
The findings provide a framework for understanding the roles of the 10 PKC family members in health and disease. Mayo Clinic is studying endoxifen in premenopausal women with estrogen receptor-positive breast cancer and plans to investigate all PKC isoforms.
Matthew Goetz, M.D., medical oncologist at Mayo Clinic Comprehensive Cancer Center: "These findings create new opportunities to develop more precise therapies for cancer and other diseases."
Matthew Schellenberg, Ph.D., molecular biologist at Mayo Clinic: "We've opened a new door. For the first time, we can see how these proteins are organized, how they function and how they may be targeted with greater precision."
Funding and Disclosures
For a complete list of authors, disclosures, and funding, refer to the study.