Page 244 - Haematologica - Vol. 105 n. 6 - June 2020

M. A.Przeradzka et al.
ary structure element does not change its conformation upon FVIII binding, which is required to detect altered deuterium incorporation.
Based on cryo-EM studies, Yee et al. proposed a model for the FVIII-D’-D3 complex. In this model the D’ domain is in contact with the FVIII C1 domain.18 The contribution of the C1 domain to VWF binding has also been demon- strated with HDX -MS studies on FVIII in the presence and of the D’-D3.19 Because of the relatively low resolu- tion of the structure, it was not possible to predict the ori- entation of the D’ domain on FVIII. Results of this study now provide evidence that the region comprising Arg782- Lys790 may be oriented towards the C1 domain of FVIII. This sequence is part of a flat surface on the TIL’ subdo- main that may optimally interact with the C1 domain (Online Supplementary Figure S4).
How the sulphated acid a3 region at the start of the FVIII A3 domain interacts with D’-D3 remains, however, unclear from both the cryo-EM study and this study. Removal of this region upon activation of FVIII is the trig- ger for FVIII-VWF complex dissociation.12 It has further
been shown that replacement of the sulphated tyrosine residue 1680 with a phenylalanine leads to a VWF binding defect.14 Recently, a well-designed nuclear magnetic reso- nance study was employed to assess the putative com- plex formation between the isolated a3 region and the iso- lated D’ domain. Main changes in chemical shift were identified outside the region that was identified in our study, i.e. residues Val772, Asn819, Cys821 and Val 822, suggesting that the a3 region may interact with these residues. The isolated a3 binds the D’ domain with a markedly reduced affinity compared to intact FVIII.36 We have also found that the VWD3 subdomain of the D3 domain is required to support D’ binding to FVIII as well.22 These notions show that the mechanism by which FVIII and VWF interact and the role of the a3 region therein remains a topic for further investigation.
Funding
This study has been funded by Product and Process Development, Sanquin, the Netherlands (PPOP-13-002) and by the Landsteiner foundation of blood research (LSBR 1882).
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