7wvx

Cryo-EM structure of the human formyl peptide receptor 2 in complex with fhumanin and Gi2

Structural highlights

7wvx is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.8Å
Ligands:	FME
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

Formyl peptide receptor 2 (FPR2) has been shown to mediate the cytotoxic effects of the beta amyloid peptide Abeta(42) and serves as a receptor for humanin, a peptide that protects neuronal cells from damage by Abeta(42), implying its involvement in the pathogenesis of Alzheimer's disease (AD). However, the interaction pattern between FPR2 and Abeta(42) or humanin remains unknown. Here we report the structures of FPR2 bound to G(i) and Abeta(42) or N-formyl humanin (fHN). Combined with functional data, the structures reveal two critical regions that govern recognition and activity of Abeta(42) and fHN, including a polar binding cavity within the receptor helical bundle and a hydrophobic binding groove in the extracellular region. In addition, the structures of FPR2 and FPR1 in complex with different formyl peptides were determined, providing insights into ligand recognition and selectivity of the FPR family. These findings uncover key factors that define the functionality of FPR2 in AD and other inflammatory diseases and would enable drug development.

Structural basis of FPR2 in recognition of Abeta(42) and neuroprotection by humanin.,Zhu Y, Lin X, Zong X, Han S, Wang M, Su Y, Ma L, Chu X, Yi C, Zhao Q, Wu B Nat Commun. 2022 Apr 1;13(1):1775. doi: 10.1038/s41467-022-29361-x. PMID:35365641^[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
↑ Zhu Y, Lin X, Zong X, Han S, Wang M, Su Y, Ma L, Chu X, Yi C, Zhao Q, Wu B. Structural basis of FPR2 in recognition of Aβ(42) and neuroprotection by humanin. Nat Commun. 2022 Apr 1;13(1):1775. PMID:35365641 doi:10.1038/s41467-022-29361-x

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] Zhu Y, Lin X, Zong X, Han S, Wang M, Su Y, Ma L, Chu X, Yi C, Zhao Q, Wu B. Structural basis of FPR2 in recognition of Aβ(42) and neuroprotection by humanin. Nat Commun. 2022 Apr 1;13(1):1775. PMID:35365641 doi:10.1038/s41467-022-29361-x

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7wvx

Cryo-EM structure of the human formyl peptide receptor 2 in complex with fhumanin and Gi2

Structural highlights

Function

Publication Abstract from PubMed

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References

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