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STRUCTURAL BIOLOGY
Molecular Jumping Jack Shows Off Moves
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Integrin's Technique Underlies Blood Clotting, Cancer Spread, Other Pivotal Events
When cells stick together they are held fast by the integrins, unique among cell surface molecules. They transmit signals across the membrane inside-out and outside-in, presumably changing its attraction for other molecules according to some complex equation. This molecular flip-flopping is accompanied by major shifts along the polypeptide backbone: loops reshape and helices slip, and the integrin "jaws"--situated in the head--bite into the knobby extracellular matrix.
Right, the integrin molecule snaps open like a switchblade from the low-affinity state, according to Junichi Takagi, Timothy Springer, Stephen Blacklow, and Natalia Beglova (l to r, above). At the "epicenter" of movement are the epiderminal growth factor (EGF)-like domains 2 and 3, located in the extreme bend of the protein in its resting state. The figure below, right, shows a surface representation of the molecule superimposed on a ribbon trace of the backbone. By solving the solution structure of these domains, the researchers could position amino acid epitopes for activating monoclonal antibodies (below, pink spheres) and amino acid residues that restrain activation (black spheres) and show that they were masked or buried in the resting state. (Photo by Pam Murray; Images adapted from originals from Timothy Springer)
Until recently integrin shape-shifting was envisioned as a jumping jack motion with the legs of the molecule splaying out and in. But last fall a partial x-ray crystal structure caught an integrin in an unexpected position: head jackknifed to legs, with its binding site tucked into the cell surface. This led to a perplexing question: How does the bent form mediate signaling?
Now in a study reported in the April Nature Structural Biology, HMS researchers have solved the puzzle. Co-lead authors Natalia Beglova and Stephen Blacklow, HMS assistant professor of pathology at Brigham and Women's Hospital, together with Junichi Takagi and Timothy Springer, the Latham Family professor of pathology at the Center for Blood Research, report a nuclear magnetic resonance (NMR) solution structure of what Springer calls the integrin "epicenter": a small yet key region of the molecule that undergoes a dramatic conformational change--a switchblade-like opening that occurs upon activation. This movement underlies the molecular mechanisms that among other things allow blood to clot, organs to develop, cancer cells to metastasize, and lymphocytes to home to infected tissue.
--Anne Mahon
Copyright 2002 by the President and Fellows of Harvard College
