Angiogenin is a well-characterized enzyme that has a variety of important roles; it can trigger the growth of new blood vessels, is involved in cell survival, migration, and proliferation, and has other functions like aiding wound healing. It's been thought that angiogenin could also be related to tumor growth, cancer and neurodegenerative disorders. However, scientists could not figure out what was activating angiogenin. Now, scientists have found an answer. Reporting in Nature, researchers have shown that the ribosome, a cellular complex well known for translating messenger RNA (mRNA) molecules into proteins, also triggers angiogenin to cleave transfer RNA (tRNA), which stops protein production.
These findings may be relevant to the development of cancer or neurodegenerative disease treatments, the study suggested. If angiogenin is going to be used therapeutically, we have to understand precisely how it is activated, noted co-corresponding study author Professor Andrei Korostelev, Ph.D of UMass Chan Medical School.
"Our work answers a long-standing question regarding angiogenin activation. We show that the ribosome binds to and changes the shape of the enzyme so it can cleave tRNA," said Korostelev.
Angiogenin was identified as an enzyme that could trigger angiogenesis, or blood vessel formation. It is a ribonuclease, meaning that it cuts RNA into smaller bits. Because it was thought to be related to cancer growth and may have helped cancer gain a blood supply, it was the subject of intense research.
Stressed cells that aren't getting enough oxygen turn to angiogenin, so new blood vessels will form and the cells can get more oxygen, noted co-corresponding study author Anna Loveland, PhD, of UMass Chan Medical School. Cancer cells use this same system. Previous work has also shown that angiogenin has neuroprotective impacts in the brain.
Since purified angiogenin only cleaved low levels of tRNA in the laboratory, researchers suspected another mechanism was helping trigger angiogenin in cells.
"Despite its fundamental biological importance and intense study, scientists haven't been able to pinpoint how angiogenin was turned on, until now," said Loveland.
In this work, the investigators had been studying the structure of the ribosome with cryo-electron microscopy. They identified another protein with one of their ribosome samples in the structure, and they noticed it resembled angiogenin. Additional work confirmed their hypothesis; there was angiogenin bound to the ribosome.
Angiogenin is usually inhibited by another protein when cells are not under stress, and the ribosome can go about its protein-constructing business. But when cells are stressed, angiogenin moves away from that inhibitor to bind to the ribosome. Once there, it nicks any incoming tRNA molecules, to stop the production of new proteins. Since protein synthesis is inhibited, other cell functions are affected as well, leading to downstream effects such as the formation of new blood vessels.
"The translation of genes into proteins is changed by this cleaving," said Korostelev. "These findings add to our understanding of how angiogenin is activated and provides an important new therapeutic target and downstream effects to investigate."
Sources: University of Massachusetts (UMass) Medical School, Nature