Advanced

Molecular Modeling of the Human Hemoglobin-Haptoglobin Complex Sheds Light on the Protective Mechanisms of Haptoglobin

Nantasenamat, Chanin; Prachayasittikul, Virapong and Bülow, Leif LU (2013) In PLoS ONE 8(4).
Abstract
Hemoglobin (Hb) plays a critical role in human physiological function by transporting O-2. Hb is safe and inert within the confinement of the red blood cell but becomes reactive and toxic upon hemolysis. Haptoglobin (Hp) is an acute-phase serum protein that scavenges Hb and the resulting Hb-Hp complex is subjected to CD163-mediated endocytosis by macrophages. The interaction between Hb and Hp is extraordinarily strong and largely irreversible. As the structural details of the human Hb-Hp complex are not yet available, this study reports for the first time on insights of the binding modalities and molecular details of the human Hb-Hp interaction by means of protein-protein docking. Furthermore, residues that are pertinent for complex... (More)
Hemoglobin (Hb) plays a critical role in human physiological function by transporting O-2. Hb is safe and inert within the confinement of the red blood cell but becomes reactive and toxic upon hemolysis. Haptoglobin (Hp) is an acute-phase serum protein that scavenges Hb and the resulting Hb-Hp complex is subjected to CD163-mediated endocytosis by macrophages. The interaction between Hb and Hp is extraordinarily strong and largely irreversible. As the structural details of the human Hb-Hp complex are not yet available, this study reports for the first time on insights of the binding modalities and molecular details of the human Hb-Hp interaction by means of protein-protein docking. Furthermore, residues that are pertinent for complex formation were identified by computational alanine scanning mutagenesis. Results revealed that the surface of the binding interface of Hb-Hp is not flat and protrudes into each binding partner. It was also observed that the secondary structures at the Hb-Hp interface are oriented as coils and alpha-helices. When dissecting the interface in more detail, it is obvious that several tyrosine residues of Hb, particularly beta 145Tyr, alpha 42Tyr and alpha 140Tyr, are buried in the complex and protected from further oxidative reactions. Such finding opens up new avenues for the design of Hp mimics which may be used as alternative clinical Hb scavengers. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
8
issue
4
publisher
Public Library of Science
external identifiers
  • wos:000318343700084
  • scopus:84876881709
ISSN
1932-6203
DOI
10.1371/journal.pone.0062996
language
English
LU publication?
yes
id
90391003-a2d6-491b-b774-febb297c4eea (old id 3821532)
date added to LUP
2013-06-25 12:15:01
date last changed
2019-03-17 04:00:57
@article{90391003-a2d6-491b-b774-febb297c4eea,
  abstract     = {Hemoglobin (Hb) plays a critical role in human physiological function by transporting O-2. Hb is safe and inert within the confinement of the red blood cell but becomes reactive and toxic upon hemolysis. Haptoglobin (Hp) is an acute-phase serum protein that scavenges Hb and the resulting Hb-Hp complex is subjected to CD163-mediated endocytosis by macrophages. The interaction between Hb and Hp is extraordinarily strong and largely irreversible. As the structural details of the human Hb-Hp complex are not yet available, this study reports for the first time on insights of the binding modalities and molecular details of the human Hb-Hp interaction by means of protein-protein docking. Furthermore, residues that are pertinent for complex formation were identified by computational alanine scanning mutagenesis. Results revealed that the surface of the binding interface of Hb-Hp is not flat and protrudes into each binding partner. It was also observed that the secondary structures at the Hb-Hp interface are oriented as coils and alpha-helices. When dissecting the interface in more detail, it is obvious that several tyrosine residues of Hb, particularly beta 145Tyr, alpha 42Tyr and alpha 140Tyr, are buried in the complex and protected from further oxidative reactions. Such finding opens up new avenues for the design of Hp mimics which may be used as alternative clinical Hb scavengers.},
  articleno    = {e62996},
  author       = {Nantasenamat, Chanin and Prachayasittikul, Virapong and Bülow, Leif},
  issn         = {1932-6203},
  language     = {eng},
  number       = {4},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Molecular Modeling of the Human Hemoglobin-Haptoglobin Complex Sheds Light on the Protective Mechanisms of Haptoglobin},
  url          = {http://dx.doi.org/10.1371/journal.pone.0062996},
  volume       = {8},
  year         = {2013},
}