{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T17:22:23Z","timestamp":1761844943457},"reference-count":42,"publisher":"Portland Press Ltd.","issue":"17","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,9,14]]},"abstract":"<jats:p>The D\u2032\u2013D3 fragment of von Willebrand factor (VWF) can be divided into TIL\u2032-E\u2032-VWD3-C8_3-TIL3-E3 subdomains of which TIL\u2032-E\u2032-VWD3 comprises the main factor VIII (FVIII)-binding region. Yet, von Willebrand disease (VWD) Type 2 Normandy (2N) mutations, associated with impaired FVIII interaction, have been identified in C8_3-TIL3-E3. We now assessed the role of the VWF (sub)domains for FVIII binding using isolated D\u2032, D3 and monomeric C-terminal subdomain truncation variants of D\u2032\u2013D3. Competitive binding assays and surface plasmon resonance analysis revealed that D\u2032 requires the presence of D3 for effective interaction with FVIII. The isolated D3 domain, however, did not show any FVIII binding. Results indicated that the E3 subdomain is dispensable for FVIII binding. Subsequent deletion of the other subdomains from D3 resulted in a progressive decrease in FVIII-binding affinity. Chemical footprinting mass spectrometry suggested increased conformational changes at the N-terminal side of D3 upon subsequent subdomain deletions at the C-terminal side of the D3. A D\u2032\u2013D3 variant with a VWD type 2N mutation in VWD3 (D879N) or C8_3 (C1060R) also revealed conformational changes in D3, which were proportional to a decrease in FVIII-binding affinity. A D\u2032\u2013D3 variant with a putative VWD type 2N mutation in the E3 subdomain (C1225G) showed, however, normal binding. This implies that the designation VWD type 2N is incorrect for this variant. Results together imply that a structurally intact D3 in D\u2032\u2013D3 is indispensable for effective interaction between D\u2032 and FVIII explaining why specific mutations in D3 can impair FVIII binding.<\/jats:p>","DOI":"10.1042\/bcj20180431","type":"journal-article","created":{"date-parts":[[2018,8,15]],"date-time":"2018-08-15T16:35:18Z","timestamp":1534350918000},"page":"2819-2830","update-policy":"http:\/\/dx.doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The D\u2032 domain of von Willebrand factor requires the presence of the D3 domain for optimal factor VIII binding"],"prefix":"10.1042","volume":"475","author":[{"given":"Ma\u0142gorzata A.","family":"Przeradzka","sequence":"first","affiliation":[{"name":"Department of Plasma Proteins, Sanquin Research, 1066 CX Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henriet","family":"Meems","sequence":"additional","affiliation":[{"name":"Department of Plasma Proteins, Sanquin Research, 1066 CX Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"van der Zwaan","sequence":"additional","affiliation":[{"name":"Department of Plasma Proteins, Sanquin Research, 1066 CX Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduard H.T.M.","family":"Ebberink","sequence":"additional","affiliation":[{"name":"Department of Plasma Proteins, Sanquin Research, 1066 CX Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maartje","family":"van den Biggelaar","sequence":"additional","affiliation":[{"name":"Department of Plasma Proteins, Sanquin Research, 1066 CX Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koen","family":"Mertens","sequence":"additional","affiliation":[{"name":"Department of Plasma Proteins, Sanquin Research, 1066 CX Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander B.","family":"Meijer","sequence":"additional","affiliation":[{"name":"Department of Plasma Proteins, Sanquin Research, 1066 CX Amsterdam, The Netherlands"},{"name":"Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2018,9,11]]},"reference":[{"key":"2021112216580125100_BCJ-2018-0431C1","doi-asserted-by":"publisher","first-page":"8752","DOI":"10.1073\/pnas.82.24.8752","article-title":"Purified human factor VIII procoagulant protein: comparative hemostatic response after infusions into hemophilic and von Willebrand disease dogs","volume":"82","author":"Brinkhous","year":"1985","journal-title":"Proc. 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