{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T07:33:21Z","timestamp":1773300801098,"version":"3.50.1"},"reference-count":56,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2012,8,21]],"date-time":"2012-08-21T00:00:00Z","timestamp":1345507200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Food and Drug Administration (MODSCI)"},{"name":"Oak Ridge Institute for Science Education (to T.L.M.)"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL47020 and GM35649 (to J.S.O.)"],"award-info":[{"award-number":["HL47020 and GM35649 (to J.S.O.)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Welch","award":["C-0612 (to J.S.O.)"],"award-info":[{"award-number":["C-0612 (to J.S.O.)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2012,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hemoglobin Brigham (\u03b2 Pro100 to Leu) was first reported in a patient with familial erythrocytosis. Erythrocytes of an affected individual from the same family contain both HbA and Hb Brigham and exhibit elevated O<jats:sub>2<\/jats:sub> affinity compared with normal cells (<jats:italic>P<\/jats:italic><jats:sub>50<\/jats:sub> = 23 mm Hg vs. 31 mmHg at pH 7.4 at 37\u00b0C). O<jats:sub>2<\/jats:sub> affinities measured for hemolysates were sensitive to changes in pH or chloride concentrations, indicating little change in the Bohr and Chloride effects. Hb Brigham was separated from normal HbA by nondenaturing cation exchange liquid chromatography, and the amino acid substitution was verified by mass spectrometry. The properties of Hb Brigham isolated from the patient's blood were then compared with those of recombinant Hb Brigham expressed in <jats:italic>Escherichia coli<\/jats:italic>. Kinetic experiments suggest that the rate constants for ligand binding and release in the high (R) and low (T) affinity quaternary states of Hb Brigham are similar to those of native hemoglobin. However, the Brigham mutation decreases the T to R equilibrium constant (<jats:italic>L<\/jats:italic>) which accelerates the switch to the R state during ligand binding to deoxy\u2010Hb, increasing the rate of association by approximately twofold, and decelerates the switch during ligand dissociation from HbO<jats:sub>2<\/jats:sub>, decreasing the rate approximately twofold. These kinetic data help explain the high O<jats:sub>2<\/jats:sub> affinity characteristics of Hb Brigham and provide further evidence for the importance of the contribution of Pro100 to intersubunit contacts and stabilization of the T quaternary structure.<\/jats:p>","DOI":"10.1002\/pro.2130","type":"journal-article","created":{"date-parts":[[2012,7,21]],"date-time":"2012-07-21T08:40:16Z","timestamp":1342860016000},"page":"1444-1455","source":"Crossref","is-referenced-by-count":3,"title":["Familial secondary erythrocytosis due to increased oxygen affinity is caused by destabilization of the T state of hemoglobin Brigham (\u03b1<sub>2<\/sub>\u03b2<sub>2<\/sub><sup>Pro100Leu<\/sup>)"],"prefix":"10.1002","volume":"21","author":[{"given":"Todd L.","family":"Mollan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bindu","family":"Abraham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael Brad","family":"Strader","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiping","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay N.","family":"Lozier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John S.","family":"Olson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdu I.","family":"Alayash","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,8,21]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.12.5675"},{"key":"e_1_2_6_3_2","first-page":"1","volume-title":"Hemoglobin: molecular, genetic, and clinical aspects","author":"Bunn H","year":"1986"},{"key":"e_1_2_6_4_2","first-page":"1","volume-title":"Hemoglobin: structure, function, evolution, and pathology","author":"Dickerson RE","year":"1983"},{"key":"e_1_2_6_5_2","unstructured":"HuismanT CarverM BaysalE EfremovG WajcmanH PatrinosG(2012) A Database of Human Hemoglobin Variants and Thalassemias. Available at:http:\/\/globin.cse.psu.edu\/. Last accessed February 13 2012."},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-04-078188"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107390"},{"key":"e_1_2_6_8_2","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1016\/S0021-9258(19)45576-2","article-title":"Subunit dissociation of the abnormal hemoglobins G Georgia (alpha2,95Leu (G2) beta2) and Rampa (alpha2,95Ser (G2) beta2)","volume":"247","author":"Smith LL","year":"1972","journal-title":"J Biol Chem"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2795(70)90117-0"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4838(89)90114-3"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1081\/HEM-120016376"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2795(80)90138-5"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-84-5-517"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.4.232"},{"key":"e_1_2_6_15_2","first-page":"49","volume-title":"Oxygen equilibrium measurements of human red blood cells. Hemoglobin disorders 82","author":"Kister J","year":"2003"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2795(73)90110-4"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biophys.27.1.1"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1993.1530"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/10.9.1085"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2005.06.012"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(93)90621-3"},{"key":"e_1_2_6_22_2","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1182\/blood.V70.5.1688.1688","article-title":"A novel globin structural mutant, Showa\u2010Yakushiji (beta 110 Leu\u2010Pro) causing a beta\u2010thalassemia phenotype","volume":"70","author":"Kobayashi Y","year":"1987","journal-title":"Blood"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.3109\/03630269308997494"},{"key":"e_1_2_6_24_2","doi-asserted-by":"crossref","first-page":"12920","DOI":"10.1016\/S0021-9258(18)45145-9","article-title":"Effect of amino acid at the beta 6 position on surface hydrophobicity, stability, solubility, and the kinetics of polymerization of hemoglobin. Comparisons among Hb A (Glu beta 6), Hb C (Lys beta 6), Hb Machida (Gln beta 6), and Hb S (Val beta 6)","volume":"262","author":"Adachi K","year":"1987","journal-title":"J Biol Chem"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4838(87)90257-3"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(87)80291-8"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/bc9700392"},{"key":"e_1_2_6_28_2","first-page":"265","volume-title":"Oxidative reactions of hemoglobin. Oxygen radicals in biological systems part b: oxygen radicals and antioxidants 186","author":"Winterbourn C","year":"1998"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4838(96)00156-2"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00748a020"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(85)91195-7"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1246-7820(05)80074-6"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)54286-1"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.3109\/03630268709042854"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.3109\/03630268108991689"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.36.23150"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)45869-9"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1080\/15216540701272380"},{"key":"e_1_2_6_39_2","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1081\/HEM-58571","article-title":"Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts","volume":"29","author":"Wajcman H","year":"2009","journal-title":"Hemoglobin"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)62533-5"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.05.036"},{"key":"e_1_2_6_42_2","doi-asserted-by":"crossref","first-page":"17248","DOI":"10.1016\/S0021-9258(18)41919-9","article-title":"A third quaternary structure of human hemoglobin A at 1.7\u2010A resolution","volume":"267","author":"Silva MM","year":"1992","journal-title":"J Biol Chem"},{"key":"e_1_2_6_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560020815"},{"key":"e_1_2_6_44_2","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1182\/blood.V31.5.623.623","article-title":"Erythrocytosis secondary to increased oxygen affinity of a mutant hemoglobin, hemoglobin kempsey","volume":"31","author":"Reed CS","year":"1968","journal-title":"Blood"},{"key":"e_1_2_6_45_2","doi-asserted-by":"crossref","first-page":"5273","DOI":"10.1016\/S0021-9258(19)41307-0","article-title":"Acceleration of tetramer formation by the binding of inositol hexaphosphate to hemoglobin dimers","volume":"250","author":"Wiedermann BL","year":"1975","journal-title":"J Biol Chem"},{"key":"e_1_2_6_46_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi011335b"},{"key":"e_1_2_6_47_2","doi-asserted-by":"crossref","first-page":"10534","DOI":"10.1016\/S0021-9258(18)81654-4","article-title":"Reactions of the protein radical in peroxide\u2010treated myoglobin: Formation of a heme\u2010protein cross\u2010link","volume":"264","author":"Catalano CE","year":"1989","journal-title":"J Biol Chem"},{"key":"e_1_2_6_48_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi200876e"},{"key":"e_1_2_6_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.200900370"},{"key":"e_1_2_6_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201000161"},{"key":"e_1_2_6_51_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.053934"},{"key":"e_1_2_6_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(81)76148-2"},{"key":"e_1_2_6_53_2","series-title":"Hemoglobins. Part C: biophysical methods","first-page":"363","author":"Mathews AJ","year":"1994"},{"key":"e_1_2_6_54_2","doi-asserted-by":"crossref","first-page":"16573","DOI":"10.1016\/S0021-9258(19)84745-2","article-title":"The effects of E7 and E11 mutations on the kinetics of ligand binding to R state human hemoglobin","volume":"264","author":"Mathews AJ","year":"1989","journal-title":"J Biol Chem"},{"key":"e_1_2_6_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)33291-X"},{"key":"e_1_2_6_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)39749-2"},{"key":"e_1_2_6_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)47338-9"}],"container-title":["Protein Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpro.2130","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpro.2130","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pro.2130","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T06:59:03Z","timestamp":1694761143000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pro.2130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,8,21]]},"references-count":56,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2012,10]]}},"alternative-id":["10.1002\/pro.2130"],"URL":"https:\/\/doi.org\/10.1002\/pro.2130","archive":["Portico"],"relation":{},"ISSN":["0961-8368","1469-896X"],"issn-type":[{"value":"0961-8368","type":"print"},{"value":"1469-896X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,8,21]]}}}