Structural basis for selectin mechanochemistry.
Selectins are adhesion molecules that resist large tensile forces applied by hydrodynamic forces to leukocytes binding to vessel walls. In crystals, the liganded (high-affinity) and unliganded (low-affinity) conformations differ in orientation between their tandem lectin and EGF domains. I examine how tensile force exerted on a selectin-ligand complex in vivo could favor the more extended, high-affinity conformation. Allostery is transmitted from the EGF-lectin domain interface to the ligand-binding interface on the lectin domain, 30 A away. Trp-1 of the lectin domain and the long axis of the EGF domain form an L-shaped prybar that is welded together by hydrogen bonds to the Trp-1 alpha-amino group. Pivoting of the prybar induced by force demolishes an interface between the Trp-1 side chain and the lectin domain at a switch1 region. These changes are transmitted by rigid body movement of the switch2 region to rearrangements in the switch3 region at the ligand binding site. Another switch region corresponds to a single residue in the EGF domain with large effects on ligand binding and rolling adhesion. Allostery in selectins, and the alignment of tensile force on a selectin-ligand complex with the transition pathway for conformational change, explain much of the structural basis for selectin mechanochemistry.
Springer
Timothy A
TA
Immune Disease Institute, Department of Pathology, Harvard Medical School, 200 Longwood Avenue, WAB Room 250, Boston, MA 02115, USA. springer@idi.harvard.edu
D000494:Allosteric Regulation; D001696:Biomechanical Phenomena; D002448:Cell Adhesion; D003198:Computer Simulation; D036904:Leukocyte Rolling; D011487:Protein Conformation; D019087:Selectins / Q000737:chemistry* / Q000502:physiology
D019087:Selectins