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BRCA – the family of DNA repair proteins badociated with bad cancers, ovarian prostate and pancreas – interacts with a multi-part molecular complex, also responsible for the regulation of the immune system . When some people on this path go wrong, autoimmune disorders, such as lupus, can occur. Researchers at the University of Pennsylvania's Perelman School of Medicine and colleagues at the University of Leeds in the UK have now deciphered the structure of the complex and discovered new molecular targets for the fight against self -immunity. Their results are published this week in Nature.
"The important badociation between this complex and the immune system was originally created because my laboratory was interested in how BRCA1 / 2 works in DNA damage reactions." Roger Greenberg, MD, PhD, professor of Cancer Biology and Director of Basic Sciences at the Bbader Center for BRCA.
An enzyme that works with BRCA1 to repair damaged DNA also exists in a separate complex called BRISC to regulate immune signaling. The Greenberg team explored the relationship between BRISC and receptors on the surface of immune cells to better understand the symptoms of lupus and other autoimmune diseases.
The overproduction of immune cells and their signaling compounds, called cytokines, causes hyperinflammation that can lead to significant tissue damage, a consequence of many autoimmune diseases. Patients with lupus, in particular, produce too much cytokine, the interferon, a natural chemical that transmits to the immune system signals that can aggravate inflammation.
Greenberg collaborated with structural biologist Elton Zeqiraj of the University of Leeds to determine the structure of the molecular complex with the help of cryo-electron microscopy (cryo-EM). Their findings revealed a fascinating molecular mechanism linking BRISC to an enzyme involved in the metabolism serine hydroxymethyltransferase 2 (SHMT2). SHMT2 guides essential reactions to basic bodily functions, such as the building blocks of proteins and DNA, after being activated by a form of vitamin B6.
By examining the complex structure of the complex, the team discovered that SHMT2 also induced immune cells to emit cytokines through its interaction with the BRISC complex. Mutations that disrupt the BRISC-SHMT2 binding zone interfere with this outbreak of inflammation, suggesting a new target for a lupus drug. This interaction was also regulated by vitamin B6 levels in the cells, providing clues about the impact of metabolism on the regulation of the immune response.
Specifically, the team solved the cryo-EM structure of the human BRISC-SHMT2 molecular complex. They discovered that it is composed of four protein subunits of the U-shaped BRISC enzyme, with different enzymatic components protruding from each side. SHMT2 bridges the gap between the two arms, blocking the active site pocket and inhibiting enzymatic activity. This block is thought to prevent abnormal BRISC activity and limit inflammatory sites to maintain immune signaling online.
Based on this work, the team plans to examine the feasibility of designing BRISC drugs to reduce the production of overactive cytokines. "We want to find a drug targeting BRISC to reduce interferon to help lupus patients," Greenberg said. "Knowing the vulnerabilities of the detailed structure of the BRISC-SHMT2 complex gives us new targets to work on."
Greenberg, Zeqiraj, in collaboration with chemist Joseph Salvino of the Wistar Institute, who also participated in this study, is developing powerful small molecule BRISC inhibitors.
"We have been working together for a decade, using a multidisciplinary approach to address some of the biggest issues in molecular biology," said Zeqiraj. "The combination of our strengths and expertise has led to some very unexpected discoveries, for which the end results are better than if we worked alone."
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