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Comment
. 2019 Aug 1;142(8):e41.
doi: 10.1093/brain/awz185.

Reply: IREB2-associated neurodegeneration

Nunziata Maio  1 , Manik C Ghosh  1 , Gregory Costain  2 , Amanda Carnevale  2 , Yue Si  3 , Grace Yoon  2   4 , Tracey A Rouault  1
Affiliations
Comment

Reply: IREB2-associated neurodegeneration

Nunziata Maio et al. Brain. .
No abstract available

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Figures

Figure 1
Figure 1
Schematic of the major contact sites between the IRE from ferritin and the apo-form of IRP1, based on the IRP1-IRE co-crystal structure (PDB: 3SNP). Apo-IRP1 undergoes a large conformational change that creates an IRE-binding pocket, in which the bulge C8 binds to a pocket in domain 4 of IRP1, two residues of the loop (G16 and A15) make finger-like binding projections into newly accessible regions of domain 3 and U17 forms a hydrogen bonds with arginine 269 in domain 2. Figure adapted from Rouault (2006).
Figure 2
Figure 2
In silico prediction of the effects of the p.(Gly785Arg) and p.(Ser444del) IREB2 mutations reported in the Australian patient on the IRE-binding affinity of IREB2. Gly785 of IREB2 corresponds to Gly710 of IRP1, which is in close proximity with the bulge C8 of the IRE element of ferritin in the IRE-IRP co-crystal (Walden et al., 2006). Substitution of glycine with the bulky and polar arginine residue (insetA) in the patient is predicted to disrupt a major IRE-IRP contact point. Deletion of serine 444 of IREB2, corresponding to cysteine 369 of IRP1, despite not affecting a highly conserved position in IREB2 sequences from different organisms, is likely to have a deleterious effect on the ability of IREB2 to bind IRE elements, because it would result in the shifting of the C-terminal residues serine 371 (corresponding to serine 446 of IREB2) and lysine 379 (corresponding to arginine 454 of IREB2) towards the N-terminus by 7.3 Å (insetB), thereby eliminating two of the most important high affinity contacts between the IRE and IRPs (the hydroxyl side chain of serine 446 to adenine 15 and the guanidinium side-chain of arginine 454 to guanine 16).
See this image and copyright information in PMC

Comment on

  • IREB2-associated neurodegeneration.
    Cooper MS, Stark Z, Lunke S, Zhao T, Amor DJ. Cooper MS, et al. Brain. 2019 Aug 1;142(8):e40. doi: 10.1093/brain/awz183. Brain. 2019. PMID: 31243445 No abstract available.

References

    1. Cooper MS, Stark Z, Lunke S, Zhao T, Amor DJ. IREB2-associated neurodegeneration. Brain 2019. doi:10.1093/brain/awz183. - PubMed
    1. Cooperman SS, Meyron-Holtz EG, Olivierre-Wilson H, Ghosh MC, McConnell JP, Rouault TA. Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2. Blood 2005; 106: 1084–91. - PMC - PubMed
    1. Costain G, Ghosh MC, Maio N, Carnevale A, Si YC, Rouault TA et al. . Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome. Brain 2019; 142: 1195–202. - PMC - PubMed
    1. Ghosh MC, Tong WH, Zhang D, Ollivierre-Wilson H, Singh A, Krishna MC et al. . Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice. Proc Natl Acad Sci USA 2008; 105: 12028–33. - PMC - PubMed
    1. Ghosh MC, Zhang DL, Rouault TA. Iron misregulation and neurodegenerative disease in mouse models that lack iron regulatory proteins. Neurobiol Dis 2015; 81: 66–75. - PMC - PubMed

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