Paper Citing NAMD - Abstract
Yago, Tadayuki; Lou, Jizhong; Wu, Tao; Yang, Jun; Miner, Jonathan J.; Coburn, Leslie; Lopez, Josd A.; Cruz, Miguel A.; Dong, Jing-Fei; McIntire, Larry V.; McEver, Rodger P.; Zhu, Cheng
Platelet glycoprotein lb alpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF
JOURNAL OF CLINICAL INVESTIGATION, 118:3195-3207, SEP 2008
Arterial blood flow enhances glycoprotein Ib alpha. (GPIb alpha) binding to vWF, which initiates platelet adhesion to injured vessels. Mutations in the vWF A1 domain that cause type 2B von Willebrand disease (vWD) reduce the flow requirement for adhesion. Here we show that increasing force on GPIb alpha/vWF bonds first prolonged ("catch") and then shortened ("slip") bond lifetimes. Two type 2B vWD Al domain mutants, R1306Q and R1450E, converted catch bonds to slip bonds by prolonging bond lifetimes at low forces. Steered molecular dynamics simulations of GPIb alpha dissociating from the Al domain suggested mechanisms for catch bonds and their conversion by the Al domain mutations. Catch bonds caused platelets and GPIb alpha-coated microspheres to roll more slowly on WT vWF and WT Al domains as flow increased from suboptimal levels, explaining flow-enhanced rolling. Longer bond lifetimes at low forces eliminated the flow requirement for rolling on R1306Q and R1450E mutant Al domains. Flowing platelets agglutinated with microspheres bearing R1306Q or R1450E mutant Al domains, but not WT Al domains. Therefore, catch bonds may prevent vWF multimers from agglutinating platelets. A disintegrin and metalloproteinase with a thrombospondin type 1 motif-13 (ADAMTS-13) reduced platelet agglutination with microspheres bearing a tridomain A1A2A3 vWF fragment with the R1450E mutation in a shear-dependent manner. We conclude that in type 2B vWD, prolonged lifetimes of vWF bonds with GPIb alpha on circulating platelets may allow ADAMTS-13 to deplete large vWF multimers, causing bleeding.
