A cis -Proline in $\alpha$-Hemoglobin Stabilizing Protein Directs the Structural Reorganization of $\alpha$-Hemoglobin

A cis -Proline in $\alpha$-Hemoglobin Stabilizing Protein Directs the Structural Reorganization of $\alpha$-Hemoglobin. Gell, D. A., Feng, L., Zhou, S., Jeffrey, P. D., Bendak, K., Gow, A., Weiss, M. J., Shi, Y., & Mackay, J. P. Journal of Biological Chemistry, 284(43):29462–29469, oct, 2009.
$A cis -Proline in $\alpha$-Hemoglobin Stabilizing Protein Directs the Structural Reorganization of $\alpha$-Hemoglobin [link]$ Paper doi abstract bibtex

$\alpha$-Hemoglobin ($\alpha$Hb) stabilizing protein (AHSP) is expressed in erythropoietic tissues as an accessory factor in hemoglobin synthesis. AHSP forms a specific complex with $\alpha$Hb and suppresses the heme-catalyzed evolution of reactive oxygen species by converting $\alpha$Hb to a conformation in which the heme is coordinated at both axial positions by histidine side chains (bis-histidyl coordination). Currently, the detailed mechanism by which AHSP induces structural changes in $\alpha$Hb has not been determined. Here, we present x-ray crystallography, NMR spectroscopy, and mutagenesis data that identify, for the first time, the importance of an evolutionarily conserved proline, Pro30, in loop 1 of AHSP. Mutation of Pro30 to a variety of residue types results in reduced ability to convert $\alpha$Hb. In complex with-Hb, AHSP Pro30 adopts a cis-peptidyl conformation and makes contact with the N terminus of helix G in $\alpha$Hb. Mutations that stabilize the cis-peptidyl conformation of free AHSP, also enhance the $\alpha$Hb conversion activity. These findings suggest that AHSP loop 1 can transmit structural changes to the heme pocket of $\alpha$Hb, and, more generally, highlight the importance of cis-peptidyl prolyl residues in defining the conformation of regulatory protein loops. \textcopyright 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

@article{Gell2009,
abstract = {$\alpha$-Hemoglobin ($\alpha$Hb) stabilizing protein (AHSP) is expressed in erythropoietic tissues as an accessory factor in hemoglobin synthesis. AHSP forms a specific complex with $\alpha$Hb and suppresses the heme-catalyzed evolution of reactive oxygen species by converting $\alpha$Hb to a conformation in which the heme is coordinated at both axial positions by histidine side chains (bis-histidyl coordination). Currently, the detailed mechanism by which AHSP induces structural changes in $\alpha$Hb has not been determined. Here, we present x-ray crystallography, NMR spectroscopy, and mutagenesis data that identify, for the first time, the importance of an evolutionarily conserved proline, Pro30, in loop 1 of AHSP. Mutation of Pro30 to a variety of residue types results in reduced ability to convert $\alpha$Hb. In complex with-Hb, AHSP Pro30 adopts a cis-peptidyl conformation and makes contact with the N terminus of helix G in $\alpha$Hb. Mutations that stabilize the cis-peptidyl conformation of free AHSP, also enhance the $\alpha$Hb conversion activity. These findings suggest that AHSP loop 1 can transmit structural changes to the heme pocket of $\alpha$Hb, and, more generally, highlight the importance of cis-peptidyl prolyl residues in defining the conformation of regulatory protein loops. {\textcopyright} 2009 by The American Society for Biochemistry and Molecular Biology, Inc.},
annote = {cited By 16},
author = {Gell, David A. and Feng, Liang and Zhou, Suiping and Jeffrey, Philip D. and Bendak, Katerina and Gow, Andrew and Weiss, Mitchell J. and Shi, Yigong and Mackay, Joel P.},
doi = {10.1074/jbc.M109.027045},
issn = {0021-9258},
journal = {Journal of Biological Chemistry},
month = {oct},
number = {43},
pages = {29462--29469},
pmid = {19706593},
title = {{A cis -Proline in $\alpha$-Hemoglobin Stabilizing Protein Directs the Structural Reorganization of $\alpha$-Hemoglobin}},
url = {http://www.jbc.org/lookup/doi/10.1074/jbc.M109.027045},
volume = {284},
year = {2009}
}

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Here, we present x-ray crystallography, NMR spectroscopy, and mutagenesis data that identify, for the first time, the importance of an evolutionarily conserved proline, Pro30, in loop 1 of AHSP. Mutation of Pro30 to a variety of residue types results in reduced ability to convert $\\alpha$Hb. In complex with-Hb, AHSP Pro30 adopts a cis-peptidyl conformation and makes contact with the N terminus of helix G in $\\alpha$Hb. Mutations that stabilize the cis-peptidyl conformation of free AHSP, also enhance the $\\alpha$Hb conversion activity. 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