Researchers reveal fail-safe structure of enzyme linked to Alzheimer’s, cancer
Like millions of Americans, Harvard Medical School postdoctoral fellow Tom Seegar struggled as he watched several family members decline from Alzheimer’s disease.
“Seeing them start to lose what we most value—our minds and ability to think—was especially painful,” he said.
Seegar’s desire to make a difference for people with Alzheimer’s helped motivate him during a five-year project to better understand a molecule linked to the disease—and lends extra meaning to what he discovered.
Working with colleagues at HMS and around the world, Seegar has revealed the atomic structure of ADAM10, a molecule that plays a critical role in healthy cell-to-cell communication but whose malfunction has also been implicated in neurodegeneration, some breast cancers and asthma.
The team’s findings, published Dec. 7 in Cell, describe a fail-safe mechanism that prevents the scissor-like ADAM10 from cutting proteins with abandon. ADAM10’s structure had a surprise in store as well.
Seeing the detailed shape of ADAM10 deepens researchers’ understanding of how the molecule works normally and provides a foundation for probing how it goes awry.
“We’re showing researchers what ADAM10 actually looks like,” said Seegar, who works in the lab of Stephen Blacklow and is first author of the study. “We need to appreciate its atomic structure to understand how it does its normal job and how it goes down a path toward dysfunction.”
The discovery sets the stage for the development of drugs that act specifically on ADAM10 to treat the diseases it fuels.
“Sometimes there’s a lag between basic research and its applications to human health, but if we don’t have a deep understanding of how fundamental biomolecules work, we’re shooting in the dark when it comes to designing therapies,” said Blacklow, the study’s senior author and the Gustavus Adolphus Pfeiffer Professor and chair of the Department of Biological Chemistry and Molecular Pharmacology at HMS.
