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Titolo:
Interspecies hybrid HbS: Complete neutralization of Val6(beta)-dependent polymerization of human beta-chain by pig alpha-chains
Autore:
Rao, MJ; Malavalli, A; Manjula, BN; Kumar, R; Prabhakaran, M; Sun, DP; Ho, NT; Ho, C; Nagel, RL; Acharya, AS;
Indirizzi:
Albert Einstein Coll Med, Div Hematol, Bronx, NY 10461 USA Albert EinsteinColl Med Bronx NY USA 10461 Hematol, Bronx, NY 10461 USA DNX Corp, Princeton, NJ 08540 USA DNX Corp Princeton NJ USA 08540DNX Corp, Princeton, NJ 08540 USA Dept Physiol & Biophys, Bronx, NY 10461 USA Dept Physiol & Biophys Bronx NY USA 10461 & Biophys, Bronx, NY 10461 USA Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA Carnegie Mellon Univ Pittsburgh PA USA 15213 ci, Pittsburgh, PA 15213 USA Struct Bioinformat, San Diego, CA 92127 USA Struct Bioinformat San Diego CA USA 92127 format, San Diego, CA 92127 USA
Titolo Testata:
JOURNAL OF MOLECULAR BIOLOGY
fascicolo: 5, volume: 300, anno: 2000,
pagine: 1389 - 1406
SICI:
0022-2836(20000728)300:5<1389:IHHCNO>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
SICKLE-CELL DISEASE; HEMOGLOBIN-S POLYMERIZATION; DEOXYHEMOGLOBIN-S; CRYSTAL-STRUCTURE; OXYGEN-AFFINITY; MOLECULAR-BASIS; GENE-THERAPY; MOUSE; INHIBITION; PROTEIN;
Keywords:
hybrid Hb; antisickling globins; gene therapy; semisynthetic chimeric alpha-chains; molecular modeling;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
59
Recensione:
Indirizzi per estratti:
Indirizzo: Acharya, AS Albert Einstein Coll Med, Div Hematol, Bronx, NY 10461 USA Albert Einstein Coll Med Bronx NY USA 10461 onx, NY 10461 USA
Citazione:
M.J. Rao et al., "Interspecies hybrid HbS: Complete neutralization of Val6(beta)-dependent polymerization of human beta-chain by pig alpha-chains", J MOL BIOL, 300(5), 2000, pp. 1389-1406

Abstract

Interspecies hybrid HbS (alpha(2)(P)beta(2)(S)), has been assembled in vitro from pig alpha-globin and human beta(S)-chain. The alpha(2)(P)beta(2)(S)retains normal tetrameric structure (alpha(2)beta(2)) of human Hb and an O-2 affinity comparable to that of HbS in 50 mM Hepes buffer; but, its O-2 affinity is slightly higher than that of HbS in the presence of allosteric effecters (chloride, DPG and phosphate). The H-1-NMR spectroscopy detected distinct differences between the heme environments and alpha(1)beta(1) interfaces of pig Hb and HbS, while their alpha(1)beta(2) interfaces appear verysimilar. The interspecies hybrid alpha(2)(H)beta(2)(P) resembles pig Hb; the pig beta-chain dictated the conformation of the heme environment of the human alpha-subunit, and to the alpha(1)beta(1) interfaces of the hybrid. In the alpha(2)(P)beta(2)(S) hybrid, beta(S)-chain dictated the conformationof human heme environment to the pig alpha-chain in the hybrid; but the conformation of alpha(1)beta(1) interface of this hybrid is close to, but notidentical to that of HbS. On the other hand, the alpha(1)beta(2) interfaceconformation is identical to that of HbS. More important, the alpha(2)(P)beta(2)(S) does not polymerize when deoxygenated; pig alpha-chain completelyneutralizes the beta(S)-chain dependent polymerization. The polymerizationinhibitory propensity of pig alpha-chain is higher when it is present in the cis alpha(P)beta(S) dimer relative to that in a trans alpha(P)beta(A) dimer. The semisynthetically generated chimeric pig-human and human-pig alpha-chains by exchanging the alpha(1-30) segments of human and pig alpha-chains have established that the sequence differences of pig alpha(31-141) segment can also completely neutralize the polymerization. Comparison of the electrostatic potential energy landscape of the alpha-chain surfaces of HbS and alpha(2)(P)beta(2)(S) suggests that the differences in electrostatic potential energy surfaces on the alpha-chain of alpha(2)(P)beta(2)(S) relative to that in HbS, particularly the ones involving CD region, E-helix and EF-corner of pig alpha-chain are responsible for the polymerization neutralization activity. The pig and human-pig chimeric alpha-chains can serve as blueprints for the design of a new generation of variants of alpha-chain(s) suitable for the gene therapy of sickle cell disease. (C) 2000 Academic Press.

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Documento generato il 29/03/20 alle ore 22:48:11