10.1021/acs.biochem.6b00617.s001
Sheetal Uppal
Sheetal
Uppal
Amit Kumar Singh
Amit
Kumar Singh
Richa Arya
Richa
Arya
Debanjan Tewari
Debanjan
Tewari
Neha Jaiswal
Neha
Jaiswal
Abhijeet Kapoor
Abhijeet
Kapoor
Amal Kanti Bera
Amal
Kanti Bera
Alo Nag
Alo
Nag
Suman Kundu
Suman
Kundu
Phe28<sup>B10</sup> Induces Channel-Forming Cytotoxic
Amyloid Fibrillation in Human Neuroglobin, the Brain-Specific Hemoglobin
American Chemical Society
2016
channel formation
brain disorders
Human Neuroglobin
Ngb ligand binding kinetics
apo states
holo form
fibril formation
Recent reports
blood hemoglobin
ambient temperature
Phe 28 B 10 Induces Channel-Forming Cytotoxic Amyloid Fibrillation
Elevated temperature
Ngb fibril
Ngb amyloid fibril
understanding amyloid-related brain disorders
holo forms
neuron-specific oxygen binding hemoglobin
neuroblastoma cell lines
ischemic stress-induced degeneration
amyloid fibril-related
amyloid formation
brain stroke
acid side chain
Phe 28 B 10
cell membrane
Brain-Specific Hemoglobin
reference hemoglobins
lipid bilayer membranes
propidium iodide uptake assay
role
novel prospect
neurodegenerative disorders
2016-11-15 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Phe28_sup_B10_sup_Induces_Channel-Forming_Cytotoxic_Amyloid_Fibrillation_in_Human_Neuroglobin_the_Brain-Specific_Hemoglobin/4269992
Since
its discovery, neuroglobin (Ngb), a neuron-specific oxygen
binding hemoglobin, distinct from the classical myoglobin and blood
hemoglobin, has attracted attention as an endogenous neuroprotectant.
Recent reports suggest that Ngb protects neurons from brain stroke,
ischemic stress-induced degeneration, and other brain disorders. Proteins
with a specific role in neuroprotection are often associated with
neurodegeneration, as well, depending on the cellular environment
or specific cellular triggers that tilt the balance one way or the
other. This investigation explored the potential role of Ngb in amyloid
fibril-related neuronal disorder. Ngb was capable of amyloid formation <i>in vitro</i> at neutral pH and ambient temperature, in both
apo and holo forms, albeit at a slower rate in the holo form, unlike
other hemoglobins that exhibit such behavior exclusively in the apo
states. Elevated temperature enhanced the rate of fibril formation
significantly. The B-helix, which is known to play a major role in
Ngb ligand binding kinetics, was found to be amyloidogenic with the
Phe28<sup>B10</sup> amino acid side chain as the key inducer of fibrillation.
The Ngb amyloid fibril was also significantly cytotoxic to neuroblastoma
cell lines, compared to those obtained from reference hemoglobins.
The Ngb fibril probably promoted toxicity by inducing channel formation
in the cell membrane, as investigated here using synthetic lipid bilayer
membranes and the propidium iodide uptake assay. These findings imply
that Ngb plays a role in neurodegenerative disorders <i>in vivo</i>, for which there seems to be indirect evidence by association. Ngb
thus presents a novel prospect for understanding amyloid-related brain
disorders beyond the limited set of proteins currently investigated
for such diseases.