Proposed model for the interaction of ADAMTS13 with the unraveled VWF A2 domain. Depicted is a model of ADAMTS13 MDTCS. The model is based on the crystal structure of ADAMTS13 DTCS¹⁷  and a homology model of MP-Dis. Surface representation is depicted and color-coded as follows: MP (red), Dis (yellow), TSP1 (green), Cys-rich (blue), and spacer (pink). The bottom figure has been rotated ∼90° compared with the top figure. The active site, Dis exosite (R349 and L350), and spacer exosite (R660, Y661, and Y665) are shown in dark red and labeled. A cartoon representation of unraveled VWF A2 domain (dashed blue ribbon) is shown to indicate how we hypothesize it extends across the ADAMTS13 active site and the exosites in the ancillary Dis, Cys-rich, and spacer domains, based on the results of mutagenesis studies. The location of the hydrophobic pocket in the Cys-rich domain involving A472, A473, and V474 is shown in red. The position of the novel glycan attachment site that impairs VWF proteolysis (Gly3) is shown in purple. In dark green is the location of the Gly2 variant glycan attachment site that had no effect on proteolysis.