{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T18:16:01Z","timestamp":1774289761395,"version":"3.50.1"},"reference-count":49,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2013,11,22]],"date-time":"2013-11-22T00:00:00Z","timestamp":1385078400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"National Heart Lung and Blood Institute of the National Institutes of Health","award":["HL109109 (to M.A.)"],"award-info":[{"award-number":["HL109109 (to M.A.)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2014,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Clinical mutations in patients diagnosed with Type 2A von Willebrand disease (VWD) have been identified that break the single disulfide bond linking N\u2010 and C\u2010termini in the vWF A1 domain. We have modeled the effect of these mutations on the disulfide\u2010bonded structure of A1 by reducing and carboxy\u2010amidating these cysteines. Solution biophysical studies show that loss of this disulfide bond induces a molten globule conformational state lacking global tertiary structure but retaining residual secondary structure. The conformational dependence of platelet adhesion to these native and molten globule states of A1 is quantitatively compared using real\u2010time high\u2010speed video microscopy analysis of platelet translocation dynamics under shear flow in a parallel plate microfluidic flow chamber. While normal platelets translocating on surface\u2010captured native A1 domain retain the catch\u2010bond character of pause times that increase as a function of shear rate at low shear and decrease as a function of shear rate at high shear, platelets that interact with A1 lacking the disulfide bond remain stably attached and do not translocate. Based on these findings, we propose that the shear stress\u2010sensitive regulation of the A1\u2010GPIb interaction is due to folding the tertiary structure of this domain. Removal of the tertiary structure by disrupting the disulfide bond destroys this regulatory mechanism resulting in high\u2010strength interactions between platelets and vWF A1 that are dependent only on residual secondary structure elements present in the molten globule conformation. Proteins 2014; 82:867\u2013878. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/prot.24464","type":"journal-article","created":{"date-parts":[[2013,11,9]],"date-time":"2013-11-09T07:56:55Z","timestamp":1383983815000},"page":"867-878","source":"Crossref","is-referenced-by-count":22,"title":["A molten globule intermediate of the Von Willebrand factor A1 domain firmly tethers platelets under shear flow"],"prefix":"10.1002","volume":"82","author":[{"given":"Alexander","family":"Tischer","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine Division of Hematology Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pranathi","family":"Madde","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine Division of Hematology Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis. M.","family":"Blancas\u2010Mejia","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Auton","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine Division of Hematology Mayo Clinic Rochester Minnesota"},{"name":"Biochemistry and Molecular Biology Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,11,22]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2011.02569.x"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.10455"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1657568"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1992.tb04595.x"},{"key":"e_1_2_6_6_1","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.1016\/S0021-9258(18)53847-3","article-title":"Disulfide bond requirements for assembly of the platelet glycoprotein Ib\u2010binding domain of von Willebrand factor","volume":"268","author":"Azuma H","year":"1993","journal-title":"J Biol Chem"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)36916-9"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00447a010"},{"key":"e_1_2_6_9_1","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1182\/blood.V84.5.1553.1553","article-title":"Structural elements influencing von Willebrand factor (vWF) binding affinity for platelet glycoprotein Ib within a dispase\u2010digested vWF fragment","volume":"84","author":"Miura S","year":"1994","journal-title":"Blood"},{"key":"e_1_2_6_10_1","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1055\/s-0038-1650599","article-title":"Characterization of recombinant von Willebrand factors mutated on cysteine 509 or 695","volume":"76","author":"Siguret V","year":"1996","journal-title":"Thromb Haemost"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.15.9046"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.10.6586"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2010.06.002"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2009.05.009"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.10.067"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09295"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.105.066548"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.2294"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)77141-5"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bioeng.10.061807.160427"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biophys.37.032807.125804"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2010.11.084"},{"key":"e_1_2_6_23_1","first-page":"3195","article-title":"Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF","volume":"118","author":"Yago T","year":"2008","journal-title":"J. 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