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Proc Natl Acad Sci U S A. 2016 Jul 26;113(30):8538-43. doi: 10.1073/pnas.1522670113. Epub 2016 Jul 12.

Globin X is a six-coordinate globin that reduces nitrite to nitric oxide in fish red blood cells.

Author information

1
Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213;
2
Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213;
3
Department of Physics and the Translational Science Center, Wake Forest University, Winston-Salem, NC 27109;
4
Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213;
5
Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15213.
6
Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213; gladwinmt@upmc.edu.

Abstract

The discovery of novel globins in diverse organisms has stimulated intense interest in their evolved function, beyond oxygen binding. Globin X (GbX) is a protein found in fish, amphibians, and reptiles that diverged from a common ancestor of mammalian hemoglobins and myoglobins. Like mammalian neuroglobin, GbX was first designated as a neuronal globin in fish and exhibits six-coordinate heme geometry, suggesting a role in intracellular electron transfer reactions rather than oxygen binding. Here, we report that GbX to our knowledge is the first six-coordinate globin and the first globin protein apart from hemoglobin, found in vertebrate RBCs. GbX is present in fish erythrocytes and exhibits a nitrite reduction rate up to 200-fold faster than human hemoglobin and up to 50-fold higher than neuroglobin or cytoglobin. Deoxygenated GbX reduces nitrite to form nitric oxide (NO) and potently inhibits platelet activation in vitro, to a greater extent than hemoglobin. Fish RBCs also reduce nitrite to NO and inhibit platelet activation to a greater extent than human RBCs, whereas GbX knockdown inhibits this nitrite-dependent NO signaling. The description of a novel, six-coordinate globin in RBCs with dominant electron transfer and nitrite reduction functionality provides new insights into the evolved signaling properties of ancestral heme-globins.

KEYWORDS:

RBC; blood; nitric oxide; nitrite; platelet

PMID:
27407144
PMCID:
PMC4968712
DOI:
10.1073/pnas.1522670113
[Indexed for MEDLINE]
Free PMC Article

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