09/06/2001
Argonne National Laboratory’s Structural Biology Center Contributes Major New Structure of Membrane Protein
The Science
Integrins are αβ heterodimeric receptors that mediate divalent cation-dependent cell-cell and cell-matrix adhesion through tightly regulated interactions with ligands. Researchers have solved the crystal structure of the extracellular portion of integrin αVβ3 at 3.1 Å resolution. Its 12 domains assemble into an ovoid “head” and two “tails.” In the crystal, αVβ3 is severely bent at a defined region in its tails, reflecting an unusual flexibility that may be linked to integrin regulation. The main inter-subunit interface lies within the head, between a seven-bladed β-propeller from αV and an A domain from β3, and bears a striking resemblance to the Gα/Gβ interface in G proteins.
Summary
A multi-institutional international team has used the Advanced Photon Source (APS) at Argonne National Laboratory (ANL) to solve for the first time the structure of an integrin. Integrins are proteins found in cell membranes that control many cellular processes and serve as a channel through which viruses can enter and infect cells. These proteins have proven extremely difficult to isolate and crystallize in order to carry out determination of their three-dimensional structures. The results are reported in Science online on September 7, 2001, and will shortly appear in the print version of this journal. The integrin studied by the group is thought to have a significant function in tumor growth and may be involved in enabling infection by the viruses responsible for AIDS and foot-and-mouth disease. The structure of the protein is complicated, with twelve domains arranged in the shape of a propeller. Thanks to the new structural information, new drugs that bind the protein can be designed that may block uptake of viruses into cells or delay growth of tumors by preventing cells from building new blood vessels to support the tumors. The team included scientists at Merck in Germany, who isolated and purified samples of the protein, at Massachusetts General Hospital and Harvard Medical School in Boston, who crystallized the protein and refined the structure, and at the BER-funded Structural Biology Center at ANL, who carried out the crystallographic experiments at their beamline at the APS.
BER Program Manager
Amy Swain
U.S. Department of Energy, Biological and Environmental Research (SC-33)
Biological Systems Science Division
[email protected]
References
Xiong, J. P., T. Stehle, B. Diefenbach, R. Zhang, R. Dunker, D. L. Scott, A. Joachimiak, S. L. Goodman, M. Amin Arnaout. 2001. “Crystal Structure of the Extracellular Segment of Integrin αVβ3,” Science 294, 339–45. DOI:10.1126/science.1064535.