Heme orientation modulates histidine dissociation and ligand binding kinetics in the hexacoordinated human neuroglobin

被引:24
作者
Bocahut, Anthony [1 ,2 ]
Derrien, Valerie [1 ]
Bernad, Sophie [1 ]
Pierre Sebban [1 ,3 ]
Sacquin-Mora, Sophie [2 ]
Guittet, Eric [4 ]
Lescop, Ewen [4 ]
机构
[1] Univ Paris 11, CNRS, UMR 8000, Chim Phys Lab, F-91405 Orsay, France
[2] CNRS, UPR 9080, Inst Biol Physicochim, Lab Biochim Theor, F-75005 Paris, France
[3] Univ Sci & Technol Hanoi, Hanoi, Vietnam
[4] CNRS, Inst Chim Subst Nat, Ctr Rech Gif, F-91190 Gif Sur Yvette, France
来源
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY | 2013年 / 18卷 / 01期
关键词
NMR; Neuroglobin; Molecular dynamics; Heme orientation; Disulfide bridge; MOLECULAR-DYNAMICS SIMULATION; DISULFIDE-BRIDGE FORMATION; HEMOGLOBIN COMPONENT-III; SPIN FERRIHEME PROTEINS; HUMAN BRAIN NEUROGLOBIN; X-RAY CRYSTALLOGRAPHY; SPERM-WHALE MYOGLOBIN; CYANIDE BINDING; STRUCTURAL DYNAMICS; MOUSE NEUROGLOBIN;
D O I
10.1007/s00775-012-0956-2
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neuroglobin (Ngb) is a globin present in the brain and retina of mammals. This hexacoordinated hemoprotein binds small diatomic molecules, albeit with lower affinity compared with other globins. Another distinctive feature of most mammalian Ngb is their ability to form an internal disulfide bridge that increases ligand affinity. As often seen for prosthetic heme b containing proteins, human Ngb exhibits heme heterogeneity with two alternative heme orientations within the heme pocket. To date, no details are available on the impact of heme orientation on the binding properties of human Ngb and its interplay with the cysteine oxidation state. In this work, we used H-1 NMR spectroscopy to probe the cyanide binding properties of different Ngb species in solution, including wild-type Ngb and the single (C120S) and triple (C46G/C55S/C120S) mutants. We demonstrate that in the disulfide-containing wild-type protein cyanide ligation is fivefold faster for one of the two heme orientations (the A isomer) compared with the other isomer, which is attributed to the lower stability of the distal His64-iron bond and reduced steric hindrance at the bottom of the cavity for heme sliding in the A conformer. We also attribute the slower cyanide reactivity in the absence of a disulfide bridge to the tighter histidine-iron bond. More generally, enhanced internal mobility in the CD loop bearing the disulfide bridge hinders access of the ligand to heme iron by stabilizing the histidine-iron bond. The functional impact of heme disorder and cysteine oxidation state on the properties of the Ngb ligand is discussed.
引用
收藏
页码:111 / 122
页数:12
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