@article {546716,
	title = {Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases.},
	journal = {Proc Natl Acad Sci USA},
	volume = {112},
	number = {15},
	year = {2015},
	pages = {4648-53},
	abstract = {Mutations\&nbsp;in the ultralong vascular protein\&nbsp;von\&nbsp;Willebrand\&nbsp;factor (VWF) cause the common human bleeding disorder,\&nbsp;von\&nbsp;Willebranddisease (VWD). The A1 domain in VWF binds to glycoprotein Ibα (GPIbα) on platelets, in a reaction triggered, in part, by alterations in flow during bleeding.\&nbsp;Gain-of-function\&nbsp;mutations\&nbsp;in A1 and GPIbα in VWD suggest conformational regulation. We report that force application switches A1 and/or GPIbα to a second state with faster\&nbsp;on-rate, providing a mechanism for activating VWF binding to platelets.\&nbsp;Switching\&nbsp;occurs near 10 pN, a force that also induces a state of the receptor-ligand complex with slower off-rate. Force greatly increases the effects of VWD\&nbsp;mutations, explaining pathophysiology. Conversion of single molecule kon (s(-1)) to bulk phase kon (s(-1)M(-1)) and the kon and koff values extrapolated to zero force for the low-force pathways show remarkably good agreement with bulk-phase measurements.\&nbsp;},
	author = {Kim, J. and <a href="http://projects.iq.harvard.edu/tas/people/nathan-hudson-phd">Hudson, N.E.</a> and Springer, T.A.}
}
