Human Brain Neuroglobin
Roman Cicero '28 and Claire Pruner '28
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I. Introduction
Globins are small respiratory proteins that reversibly bind O2 by means of an iron-containing porphyrin ring. In man and other vertebrates, red blood cell hemoglobin transports O2 in the circulatory system. Myoglobin facilitates O2 diffusion, typically in the cardiac and striated muscles. Human Brain Neuroglobin is a member of the vertebrate globin family, and is found mainly in the central and peripheral nervous system, as well as some endocrine tissues. It is also highly expressed in the mammalian retina, one of the highest oxygen-consuming tissues of the body.
Human Brain Neuroglobin’s primary function is to deliver oxygen to nervous tissue. It is thought to act as a neuroprotective factor in response to hypoxic conditions. It is also believed to protect the retina from O2 deprivation. Neuroglobin is capable of this specialized role in the nervous system due to its efficiency, compared to other globins, at binding and delivering oxygen. This efficiency is essential as neurons require large amounts of oxygen and are highly vulnerable to hypoxia.
II. General Structure
Human Brain Neuroglobin is a monomeric protein made up of 151 residues with a total structural weight of 17.64 kDa. Neuroglobin is composed of 8 α-helices . The protein folding of these helices conform to the classical three-over-three a-helical sandwich also observed in mammalian hemoglobin and myoglobin. This is formed by helices A, B, E, and F, G, H. Helices C and D form the CD region finalizing the formation of the globin fold. The in neuroglobin is seen to protrude from the protein core, deviating by more than 2.0 Å from what is observed in the structurally equivalent region in myoglobin. Another structurally relevant region is the EF loop. The flexibility in both regions aids in the histidine-promoted conformational change in response to oxygen binding.
The helices are oriented so that an inner core is formed by hydrophobic residues, while hydrophilic residues are oriented facing the solvent. This stabilizes the structure and, in combination with the three-over-three sandwich, serves to create an internal cavity. This cavity holds a hexacoordinated which is composed of an iron ion stabilized by a porphyrin ring and two covalent bonds to the NE2 nitrogens of histidine residues on neighboring . The distal HisE7 (helix E) imidazole ring is almost perfectly staggered relative to the heme pyrrole N atoms. HisE7 coordination with the heme shifts the E helix toward the heme by about 3 Å relative to myoglobin. This makes the distal region crowded when in combination with supporting Phe(28), Phe(42), Val(68) residues, and a Lys(67)-heme propionate . The proximal HisF8 residue is also staggered to the heme pyrrole N atoms. The bihistidyl nature of the heme allows the iron ion to sit nearly flat in the heme plane making it easier for oxygen to bind to the distal side.
The inner cavity is formed by the residues Val(71), Ala(74), between Leu(85) and Tyr(88), and the side chains of Leu(136) and Tyr(137) They are from the helices B, E, G and H. This generates an elongated matrix compared to other globins. The resulting structure offers an efficient diffusion path for oxygen from the solvent to the heme iron ion.
III. Oxygen Binding
The main function of neuroglobin is to bind oxygen. Neuroglobin does this reversibly through interactions between the heme iron ion and oxygen that diffuses through the elongated protein matrix cavity.
Figure 3. Ligand pathways in globins. A. depicts neuroglobin. B. compared to a globin identified in the nerve tissue of the nemertean worm Cerebratulus lacteus (from Trends in Biochemical Sciences, 2003).
Reproduced from Trends in Biochemical Sciences, © Elsevier.
The oxygen binding efficiency of neuroglobin stems from this elongated cavity. It remains largely uninterrupted and is structurally stabilized by lining residues. In comparison, hemoglobin and myoglobin have smaller, interrupted cavities.
After entering the cavity, oxygen diffuses to the heme iron ion and transiently binds, displacing Histidine E7. The Histidine E7 outfolding from the distal pocket and escape from the heme iron ion coordination sphere is facilitated by the flexibility of the CD region and EF loop. This facilitation is necessary as the of the Histidine residue must overcome the interactions between the porphyrin ring and the Lys(67)-heme ion pairing. While the oxygen atom is bound, the iron ion is bound only to the porphyrin ring and one DNA helix through HisF8 for a total of five of the original six bonds. The original hexacoordinated heme, in which the sixth ligand is now displaced by oxygen, allows for rapid binding of O2 and a higher affinity for it. Thus, neuroglobin has a simple yet powerful mechanism to facilitate O2 binding.
IV. Potential Applications of Neuroglobin
As mentioned previously, neuroglobin is particularly suited to carry oxygen in hypoxic environments, supplying neurons with needed oxygen and staving off neuron death. Furthermore, recent studies have shown that neuroglobin could also be instrumental in helping treat neurological diseases and mediating the harms of traumatic brain injuries. Under hypoxic conditions, large amounts of reactive oxygen species are formed in the body due to metabolic disruption. Studies have shown that neuroglobin reduces the effect of oxidative stress by mitigating the accumulation of reactive oxygen species, increasing cell survival. It is hypothesized that this function of neuroglobin is related to other radical scavengers that are known in the body. However, the specific mechanism of this function in neuroglobin is still largely being researched. Despite this research still being in its early stages, these findings suggest that neuroglobin may have applications in preventing neurological diseases that involve neuron death, such as dementia, and overall make it a strong candidate for mediating central nervous system diseases in the future.
V. References
Alessandra Pesce, Sylvia Dewilde, Marco Nardini, Luc Moens, Paolo Ascenzi, Thomas Hankeln, Thorsten Burmester, Martino Bolognesi, Human Brain Neuroglobin Structure Reveals a Distinct Mode of Controlling Oxygen Affinity. Structure, Volume 11, Issue 9, 2003. Pages 1087-1095, ISSN 0969-2126, https://doi.org/10.1016/S0969-2126(03)00166-7.
Yañez IM, Torres-Cuevas I, Corral-Debrinski M. Neuroglobin: A promising candidate to treat neurological diseases. Neural Regen Res. 2026 Apr 1;21(4):1292-1303. doi: 10.4103/NRR.NRR-D-24-01503. Epub 2025 Jun 19. PMID: 40536996; PMCID: PMC12407527.
Li RC, Morris MW, Lee SK, Pouranfar F, Wang Y, Gozal D. Neuroglobin protects PC12 cells against oxidative stress. Brain Res. 2008 Jan 23;1190:159-66. doi: 10.1016/j.brainres.2007.11.022. Epub 2007 Nov 22. PMID: 18083144; PMCID: PMC2323248.
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