{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T07:29:26Z","timestamp":1775806166830,"version":"3.50.1"},"reference-count":51,"publisher":"American Society of Hematology","issue":"19","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,5,9]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Activation of von Willebrand factor (VWF) is a tightly controlled process governed primarily by local elements around its A1 domain. Recent studies suggest that the O-glycosylated sequences flanking the A1 domain constitute a discontinuous and force-sensitive autoinhibitory module (AIM), although its extent and conformation remains controversial. Here, we used a targeted screening strategy to identify 2 groups of nanobodies. One group, represented by clone 6D12, is conformation insensitive and binds the N-terminal AIM (NAIM) sequence that is distal from A1; 6D12 activates human VWF and induces aggregation of platelet-rich plasma at submicromolar concentrations. The other group, represented by clones Nd4 and Nd6, is conformation sensitive and targets the C-terminal AIM (CAIM). Nd4 and Nd6 inhibit ristocetin-induced platelet aggregation and reduce VWF-mediated platelet adhesion under flow. A crystal structure of Nd6 in complex with AIM-A1 shows a novel conformation of both CAIM and NAIM that are primed to interact, providing a model of steric hindrance stabilized by the AIM as the mechanism for regulating GPIb\u03b1 binding to VWF. Hydrogen-deuterium exchange mass spectrometry analysis shows that binding of 6D12 induces the exposure of the GPIb\u03b1-binding site in the A1 domain, but binding of inhibitory nanobodies reduces it. Overall, these results suggest that the distal portion of NAIM is involved in specific interactions with CAIM, and binding of nanobodies to the AIM could either disrupt its conformation to activate VWF or stabilize its conformation to upkeep VWF autoinhibition. These reported nanobodies could facilitate future studies of VWF functions and related pathologies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023022038","type":"journal-article","created":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T21:31:36Z","timestamp":1706650296000},"page":"1992-2004","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":9,"title":["Conformational activation and inhibition of von Willebrand factor by targeting its autoinhibitory module"],"prefix":"10.1182","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0019-0380","authenticated-orcid":false,"given":"Nicholas A.","family":"Arce","sequence":"first","affiliation":[{"name":"1Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8048-0926","authenticated-orcid":false,"given":"Zoe","family":"Markham-Lee","sequence":"additional","affiliation":[{"name":"2Biodiscovery Institute, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3985-2633","authenticated-orcid":false,"given":"Qian","family":"Liang","sequence":"additional","affiliation":[{"name":"1Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA"},{"name":"3Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0429-5454","authenticated-orcid":false,"given":"Shabir","family":"Najmudin","sequence":"additional","affiliation":[{"name":"2Biodiscovery Institute, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom"}]},{"given":"Emily R.","family":"Legan","sequence":"additional","affiliation":[{"name":"1Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA"}]},{"given":"Gabrielle","family":"Dean","sequence":"additional","affiliation":[{"name":"1Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6447-3438","authenticated-orcid":false,"given":"Ally J.","family":"Su","sequence":"additional","affiliation":[{"name":"1Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3687-0078","authenticated-orcid":false,"given":"Moriah S.","family":"Wilson","sequence":"additional","affiliation":[{"name":"1Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9509-9415","authenticated-orcid":false,"given":"Robert F.","family":"Sidonio","sequence":"additional","affiliation":[{"name":"1Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1206-8104","authenticated-orcid":false,"given":"Pete","family":"Lollar","sequence":"additional","affiliation":[{"name":"1Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8949-8030","authenticated-orcid":false,"given":"Jonas","family":"Emsley","sequence":"additional","affiliation":[{"name":"2Biodiscovery Institute, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5806-5080","authenticated-orcid":false,"given":"Renhao","family":"Li","sequence":"additional","affiliation":[{"name":"1Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA"}]}],"member":"234","reference":[{"key":"2024050915204650400_bib1","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1146\/annurev.biochem.67.1.395","article-title":"Biochemistry and genetics of von Willebrand factor","volume":"67","author":"Sadler","year":"1998","journal-title":"Annu Rev Biochem"},{"issue":"9","key":"2024050915204650400_bib2","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1182\/blood-2014-05-378638","article-title":"von Willebrand factor, Jedi knight of the 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