5giw

Solution NMR structure of Humanin containing a D-isomerized serine residue

Structural highlights

5giw is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	DSN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HUNIN_HUMAN Plays a role as a neuroprotective factor. Protects against death induced by multiple different familial Alzheimer disease genes and beta amyloid proteins in Alzheimer disease. Suppresses apoptosis by binding to BAX and preventing the translocation of BAX from the cytosol to mitochondria. Binds to IGFBP3 and specifically blocks IGFBP3-induced cell death Induces chemotaxis of mononuclear phagocytes via FPR2. Reduces the aggregation and fibrillary formation by suppressing the effect of APP on mononuclear phagocytes and acts by competitively inhibiting the access of FPRL1 to APP.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Humanin comprising 24 amino acid residues is a bioactive peptide that has been isolated from the brain tissue of patients with Alzheimer's disease. Humanin reportedly suppressed aging-related death of various cells due to amyloid fibrils and oxidative stress. There are reports that the cytoprotective activity of Humanin was remarkably enhanced by optical isomerization of the Ser14 residue from l to d form, but details of the molecular mechanism remained unclear. Here we demonstrated that Humanin d-Ser14 exhibited potent inhibitory activity against fibrillation of amyloid-beta and remarkably higher binding affinity for amyloid-beta than that of the Humanin wild-type and S14G mutant. In addition, we determined the solution structure of Humanin d-Ser14 by nuclear magnetic resonance (NMR) and showed that d-isomerization of the Ser14 residue enables drastic conformational rearrangement of Humanin. Furthermore, we identified an amyloid-beta-binding site on Humanin d-Ser14 at atomic resolution by NMR. These biophysical and high-resolution structural analyses clearly revealed structure-function relationships of Humanin and explained the driving force of the drastic conformational change and molecular basis of the potent anti-amyloid-beta fibrillation activity of Humanin caused by d-isomerization of the Ser14 residue. This is the first study to show correlations between the functional activity, tertiary structure, and partner recognition mode of Humanin and may lead to elucidation of the molecular mechanisms of the cytoprotective activity of Humanin.

Solution NMR structure and inhibitory effect against amyloid-beta fibrillation of Humanin containing a d-isomerized serine residue.,Alsanousi N, Sugiki T, Furuita K, So M, Lee YH, Fujiwara T, Kojima C Biochem Biophys Res Commun. 2016 Jun 25. pii: S0006-291X(16)31032-4. doi:, 10.1016/j.bbrc.2016.06.114. PMID:27349871^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6336-41. PMID:11371646 doi:10.1073/pnas.101133498
↑ Ikonen M, Liu B, Hashimoto Y, Ma L, Lee KW, Niikura T, Nishimoto I, Cohen P. Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13042-7. Epub 2003 Oct 15. PMID:14561895 doi:https://dx.doi.org/10.1073/pnas.2135111100
↑ Hashimoto Y, Niikura T, Ito Y, Sudo H, Hata M, Arakawa E, Abe Y, Kita Y, Nishimoto I. Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults. J Neurosci. 2001 Dec 1;21(23):9235-45. PMID:11717357
↑ Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, Reed JC. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 2003 May 22;423(6938):456-61. Epub 2003 May 4. PMID:12732850 doi:https://dx.doi.org/10.1038/nature01627
↑ Ying G, Iribarren P, Zhou Y, Gong W, Zhang N, Yu ZX, Le Y, Cui Y, Wang JM. Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor. J Immunol. 2004 Jun 1;172(11):7078-85. PMID:15153530
↑ Alsanousi N, Sugiki T, Furuita K, So M, Lee YH, Fujiwara T, Kojima C. Solution NMR structure and inhibitory effect against amyloid-beta fibrillation of Humanin containing a d-isomerized serine residue. Biochem Biophys Res Commun. 2016 Jun 25. pii: S0006-291X(16)31032-4. doi:, 10.1016/j.bbrc.2016.06.114. PMID:27349871 doi:https://dx.doi.org/10.1016/j.bbrc.2016.06.114

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6336-41. PMID:11371646 doi:10.1073/pnas.101133498

[2] Ikonen M, Liu B, Hashimoto Y, Ma L, Lee KW, Niikura T, Nishimoto I, Cohen P. Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13042-7. Epub 2003 Oct 15. PMID:14561895 doi:https://dx.doi.org/10.1073/pnas.2135111100

[3] Hashimoto Y, Niikura T, Ito Y, Sudo H, Hata M, Arakawa E, Abe Y, Kita Y, Nishimoto I. Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults. J Neurosci. 2001 Dec 1;21(23):9235-45. PMID:11717357

[4] Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, Reed JC. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 2003 May 22;423(6938):456-61. Epub 2003 May 4. PMID:12732850 doi:https://dx.doi.org/10.1038/nature01627

[5] Ying G, Iribarren P, Zhou Y, Gong W, Zhang N, Yu ZX, Le Y, Cui Y, Wang JM. Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor. J Immunol. 2004 Jun 1;172(11):7078-85. PMID:15153530

[6] Alsanousi N, Sugiki T, Furuita K, So M, Lee YH, Fujiwara T, Kojima C. Solution NMR structure and inhibitory effect against amyloid-beta fibrillation of Humanin containing a d-isomerized serine residue. Biochem Biophys Res Commun. 2016 Jun 25. pii: S0006-291X(16)31032-4. doi:, 10.1016/j.bbrc.2016.06.114. PMID:27349871 doi:https://dx.doi.org/10.1016/j.bbrc.2016.06.114

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5giw

Solution NMR structure of Humanin containing a D-isomerized serine residue

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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