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Protein Science (2004), 13:1266-1275. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Hemoglobin Einstein: Semisynthetic deletion in the B-helix of the {alpha}-chain

Sonati Srinivasulu1, Belur N. Manjula2, Ronald L. Nagel1, Ching-Hsuan Tsai3, Chien Ho3, Muthuchidambaran Prabhakaran1 and Seetharama A. Acharya1,2

1 Departments of Medicine and of
2 Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
3 Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA

(RECEIVED December 12, 2003; FINAL REVISION February 3, 2004; ACCEPTED February 3, 2004)



Abstract

The influence of the deletion of the tetra peptide segment {alpha}23–26 of the B-helix of the {alpha}-chain of hemoglobin-A on its assembly, structure, and functional properties has been investigated. The hemoglobin with the deletion, ss-Hemoglobin-Einstein, is readily assembled from semisynthetic {alpha}1–141 des23–26 globin and human {beta}A-chain. The deletion of {alpha}23–26 modulates the O2 affinity of hemoglobin in a buffer/allosteric effector specific fashion, but has little influence on the Bohr effect. The deletion has no influence on the thermodynamic stability of the {alpha}1{beta}1 and the {alpha}1{beta}2 interface. The semisynthetic hemoglobin exhibits normal intersubunit interactions at the {alpha}1{beta}1 and {alpha}1{beta}2 interfaces as reflected by 1H-NMR spectroscopy. Molecular modeling studies of ss-Hemoglobin-Einstein suggest that the segment {alpha}28–35 is in a helical conformation, while the segment {alpha}19–22 is the nonhelical AB region. The shortened B-helix conserves the interactions of {alpha}1{beta}1 interface. The results demonstrate a high degree of plasticity in the hemoglobin structure that accommodates the deletion of {alpha}23–26 without perturbing its overall global conformation.

Keywords: shortened B-helix; stuctural plasticity; thermodynamic stability; subunit interfaces; oxygen affinity; 1H-NMR spectroscopy; molecular modeling

Abbreviations: ss-Hb, semisynthetic hemoglobin • HbA, human adult hemoglobin • RP-HPLC, reverse-phase high-performance liquid chromatography • kD, kilodaltons • HMB, p-hydroxymercuri benzoiate • NMR, nuclear magnetic resonance • DSS, dimethyl-2-silapentane 5-sulfonate • IEF, iso-electric focusing • HbCOA, carbon monoxy HbA • DPG, 2,3 diphosphoglyceric acid, IHP, inositol hexaphosphate • L-35, 3,5-dichloro phenylureido-phenoxy isobutyric acid • HEPES, N-(2-hydroxyethyl) piperazine -N-(2-ethane sulfonic acid)

Reprint requests to: Seetharama A. Acharya, Departments of Medicine and of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; e-mail: acharya{at}aecom.yu.edu (718) 824-3153.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03567804.


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