Uncovering a Latent Bioactive Interleukin-6 Glycoform

Liu, Yanbo; Maki, Yuta; Okamoto, Ryo; Satoh, Ayano; Todokoro, Yasuto; Kanemitsu, Yurie; Otani, Keito; Kajihara, Yasuhiro

doi:https://doi.org/10.1002/anie.202411213

Uncovering a Latent Bioactive Interleukin-6 Glycoform

Liu, Yanbo; Maki, Yuta; Okamoto, Ryo et al.

Angewandte Chemie - International Edition, 2024, 63(50), e202411213

アクセス数:980件（2026-02-16 12:11 集計）

固定URL: https://hdl.handle.net/11094/98891

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タイトル	Uncovering a Latent Bioactive Interleukin-6 Glycoform
著者	著者名 Liu, Yanbo
	NRID 1000000805559 1000000805559 researchmap permalink ymou ymou Scopus Author ID 57188724477 57188724477 著者名 Maki, Yuta
	NRID 1000030596870 1000030596870 ORCID 0000-0001-9529-2525 0000-0001-9529-2525 researchmap permalink ryookamoto ryookamoto Scopus Author ID 36194293500 36194293500 著者名 Okamoto, Ryo
	NRID 1000040303002 1000040303002 著者名 Satoh, Ayano
	researchmap permalink todokoro todokoro Scopus Author ID 7003896111 7003896111 著者名 Todokoro, Yasuto
	著者名 Kanemitsu, Yurie
	著者名 Otani, Keito
	NRID 1000050275020 1000050275020 ORCID 0000-0002-6656-2394 0000-0002-6656-2394 researchmap permalink read0048540 read0048540 Scopus Author ID 7006984179 7006984179 著者名 Kajihara, Yasuhiro
キーワード等	Glycoprotein
	Interleukin 6
	Protein aggregation
	Protein folding chemistry
	Protein synthesis
内容	Liu Y., Maki Y., Okamoto R., et al. Uncovering a Latent Bioactive Interleukin-6 Glycoform. Angewandte Chemie - International Edition 63, e202411213 (2024); https://doi.org/10.1002/anie.202411213.
抄録	A bioinspired semisynthesis of human-interleukin-6 bearing N-glycan at Asn143 (143glycosyl-IL-6) was performed by intentional glycosylation effects and protein folding chemistry for regioselective peptide-backbone activation. 143Glycosyl-IL-6 is a genetically coded cytokine, but isolation was difficult owing to a tiny amount. IL6-polypeptide (1–141-position) with an intentionally inserted cysteine at 142-position was expressed in E. coli. The expressed polypeptide was treated with a chemical folding process to make a specific helices bundle conformation through native two-disulfide bonds (43–49 and 72–82). Utilizing the successfully formed free-142-cysteine, sequential conversions using cyanylation of 142-cysteine, hydrazinolysis, and thioesterification created a long polypeptide (1–141)-thioester. However, the resultant polypeptide-thioester caused considerable aggregation owing to a highly hydrophobic peptide sequence. After the reduction of two-disulfide bonds of polypeptide (1–141)-thioester, an unprecedented hydrophilic N-glycan tag was inserted at the resultant cysteine thiols. The N-glycan tags greatly stabilized polypeptide-thioester. The subsequent native chemical ligation and desulfurization successfully gave a whole 143glycosyl-IL-6 polypeptide (183-amino acids). Removal of four N-glycan tags and immediate one-pot in vitro folding protocol efficiently produced the folded 143glycosyl-IL-6. The folded 143glycosyl-IL-6 exhibited potent cell proliferation activity. The combined studies with molecular dynamics simulation, semisynthesis, and bioassays predict the bioactive conformation of latent 143glycosyl-IL-6.
出版者	John Wiley and Sons Inc
収録物名	Angewandte Chemie - International Edition
巻(号)	63(50)
ページ	e202411213
刊行年月	2024-12-09
言語	英語
ハンドルURL	https://hdl.handle.net/11094/98891
PISSN	14337851
eISSN	15213773
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1002/anie.202411213
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCTERMS.bibliographicCitation	Angewandte Chemie - International Edition. 2024, 63(50), p. e202411213
DC.title	Uncovering a Latent Bioactive Interleukin-6 Glycoform
DC.creator	Liu, Yanbo
	Maki, Yuta
	Okamoto, Ryo
	Satoh, Ayano
	Todokoro, Yasuto
	Kanemitsu, Yurie
	Otani, Keito
	Kajihara, Yasuhiro
DC.publisher	John Wiley and Sons Inc
DC.language' scheme='DCTERMS.RFC1766	英語
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-12-09
DC.identifier	https://doi.org/10.1002/anie.202411213
DC.subject	Glycoprotein
	Interleukin 6
	Protein aggregation
	Protein folding chemistry
	Protein synthesis
DC.description	Liu Y., Maki Y., Okamoto R., et al. Uncovering a Latent Bioactive Interleukin-6 Glycoform. Angewandte Chemie - International Edition 63, e202411213 (2024); https://doi.org/10.1002/anie.202411213.
DCTERMS.abstract	A bioinspired semisynthesis of human-interleukin-6 bearing N-glycan at Asn143 (143glycosyl-IL-6) was performed by intentional glycosylation effects and protein folding chemistry for regioselective peptide-backbone activation. 143Glycosyl-IL-6 is a genetically coded cytokine, but isolation was difficult owing to a tiny amount. IL6-polypeptide (1–141-position) with an intentionally inserted cysteine at 142-position was expressed in E. coli. The expressed polypeptide was treated with a chemical folding process to make a specific helices bundle conformation through native two-disulfide bonds (43–49 and 72–82). Utilizing the successfully formed free-142-cysteine, sequential conversions using cyanylation of 142-cysteine, hydrazinolysis, and thioesterification created a long polypeptide (1–141)-thioester. However, the resultant polypeptide-thioester caused considerable aggregation owing to a highly hydrophobic peptide sequence. After the reduction of two-disulfide bonds of polypeptide (1–141)-thioester, an unprecedented hydrophilic N-glycan tag was inserted at the resultant cysteine thiols. The N-glycan tags greatly stabilized polypeptide-thioester. The subsequent native chemical ligation and desulfurization successfully gave a whole 143glycosyl-IL-6 polypeptide (183-amino acids). Removal of four N-glycan tags and immediate one-pot in vitro folding protocol efficiently produced the folded 143glycosyl-IL-6. The folded 143glycosyl-IL-6 exhibited potent cell proliferation activity. The combined studies with molecular dynamics simulation, semisynthesis, and bioassays predict the bioactive conformation of latent 143glycosyl-IL-6.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	98891
citation_title	Uncovering a Latent Bioactive Interleukin-6 Glycoform
citation_author	Liu, Yanbo
	Maki, Yuta
	Okamoto, Ryo
	Satoh, Ayano
	Todokoro, Yasuto
	Kanemitsu, Yurie
	Otani, Keito
	Kajihara, Yasuhiro
citation_publisher	John Wiley and Sons Inc
citation_language	英語
citation_date	2024-12-09
citation_journal_title	Angewandte Chemie - International Edition
citation_volume	63
citation_issue	50
citation_firstpage	e202411213
citation_doi	https://doi.org/10.1002/anie.202411213
citation_public_url	https://hdl.handle.net/11094/98891

Uncovering a Latent Bioactive Interleukin-6 Glycoform

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