Structure, Folding Dynamics, and Amyloidogenesis of D76N β2-Microglobulin : ROLES OF SHEAR FLOW, HYDROPHOBIC SURFACES, AND α-CRYSTALLIN

Mangione, P. Patrizia; Esposito, Gennaro; Relini, Annalisa; Raimondi, Sara; Porcari, Riccardo; Giorgetti, Sofia; Corazza, Alessandra; Fogolari, Federico; Penco, Amanda; Goto, Yuji; Lee, Young-Ho; Yagi, Hisashi; Cecconi, Ciro; Naqvi, Mohsin M.; Gillmore, Julian D.; Hawkins, Philip N.; Chiti, Fabrizio; Rolandi, Ranieri; Taylor, Graham W.; Pepys, Mark B.; Stoppini, Monica; Bellotti, Vittorio

doi:https://doi.org/10.1074/jbc.M113.498857

Structure, Folding Dynamics, and Amyloidogenesis of D76N β2-Microglobulin : ROLES OF SHEAR FLOW, HYDROPHOBIC SURFACES, AND α-CRYSTALLIN

Mangione, P. Patrizia; Esposito, Gennaro; Relini, Annalisa et al.

Journal of Biological Chemistry, 2013, 288(43), 30917-30930

Number of Access:1,141（2025-08-30 11:33 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/71279

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Title	Structure, Folding Dynamics, and Amyloidogenesis of D76N β2-Microglobulin : ROLES OF SHEAR FLOW, HYDROPHOBIC SURFACES, AND α-CRYSTALLIN
Creator	CreatorName Mangione, P. Patrizia
	CreatorName Esposito, Gennaro
	CreatorName Relini, Annalisa
	CreatorName Raimondi, Sara
	CreatorName Porcari, Riccardo
	CreatorName Giorgetti, Sofia
	CreatorName Corazza, Alessandra
	CreatorName Fogolari, Federico
	CreatorName Penco, Amanda
	NRID 1000040153770 1000040153770 researchmap permalink read0014440 read0014440 CreatorName Goto, Yuji
	NRID 1000070589431 1000070589431 CreatorName Lee, Young-Ho
	NRID 1000010432494 1000010432494 CreatorName Yagi, Hisashi
	CreatorName Cecconi, Ciro
	CreatorName Naqvi, Mohsin M.
	CreatorName Gillmore, Julian D.
	CreatorName Hawkins, Philip N.
	CreatorName Chiti, Fabrizio
	CreatorName Rolandi, Ranieri
	CreatorName Taylor, Graham W.
	CreatorName Pepys, Mark B.
	CreatorName Stoppini, Monica
	CreatorName Bellotti, Vittorio
Description	This research was originally published in the Journal of Biological Chemistry. P. Patrizia Mangione, Gennaro Esposito, Annalisa Relini, Sara Raimondi, Riccardo Porcari, Sofia Giorgetti, Alessandra Corazza, Federico Fogolari, Amanda Penco, Yuji Goto, Young-Ho Lee, Hisashi Yagi, Ciro Cecconi, Mohsin M. Naqvi, Julian D. Gillmore, Philip N. Hawkins, Fabrizio Chiti, Ranieri Rolandi, Graham W. Taylor, Mark B. Pepys, Monica Stoppini and Vittorio Bellotti. Structure, Folding Dynamics, and Amyloidogenesis of D76N β2-Microglobulin: ROLES OF SHEAR FLOW, HYDROPHOBIC SURFACES, AND α-CRYSTALLIN. J. Biol. Chem. 2013; 288, 30917–30930. © the American Society for Biochemistry and Molecular Biology
Abstract	Systemic amyloidosis is a fatal disease caused by misfolding of native globular proteins, which then aggregate extracellularly as insoluble fibrils, damaging the structure and function of affected organs. The formation of amyloid fibrils in vivo is poorly understood. We recently identified the first naturally occurring structural variant, D76N, of human β2-microglobulin (β2m), the ubiquitous light chain of class I major histocompatibility antigens, as the amyloid fibril protein in a family with a new phenotype of late onset fatal hereditary systemic amyloidosis. Here we show that, uniquely, D76N β2m readily forms amyloid fibrils in vitro under physiological extracellular conditions. The globular native fold transition to the fibrillar state is primed by exposure to a hydrophobic-hydrophilic interface under physiological intensity shear flow. Wild type β2m is recruited by the variant into amyloid fibrils in vitro but is absent from amyloid deposited in vivo. This may be because, as we show here, such recruitment is inhibited by chaperone activity. Our results suggest general mechanistic principles of in vivo amyloid fibrillogenesis by globular proteins, a previously obscure process. Elucidation of this crucial causative event in clinical amyloidosis should also help to explain the hitherto mysterious timing and location of amyloid deposition.
Publisher	American Society for Biochemistry and Molecular Biology
Source Title	Journal of Biological Chemistry
Volume (Issue)	288(43)
Page	30917-30930
Date of Issued	2013-10
Language	English
Handle URL	https://hdl.handle.net/11094/71279
eISSN	1083351X
NCID	AA1202448X
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1074/jbc.M113.498857
Access Rights	open access
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Journal of Biological Chemistry. 2013, 288(43), p. 30917-30930
DC.title	Structure, Folding Dynamics, and Amyloidogenesis of D76N β2-Microglobulin : ROLES OF SHEAR FLOW, HYDROPHOBIC SURFACES, AND α-CRYSTALLIN
DC.creator	Mangione, P. Patrizia
	Esposito, Gennaro
	Relini, Annalisa
	Raimondi, Sara
	Porcari, Riccardo
	Giorgetti, Sofia
	Corazza, Alessandra
	Fogolari, Federico
	Penco, Amanda
	Goto, Yuji
	Lee, Young-Ho
	Yagi, Hisashi
	Cecconi, Ciro
	Naqvi, Mohsin M.
	Gillmore, Julian D.
	Hawkins, Philip N.
	Chiti, Fabrizio
	Rolandi, Ranieri
	Taylor, Graham W.
	Pepys, Mark B.
	Stoppini, Monica
	Bellotti, Vittorio
DC.publisher	American Society for Biochemistry and Molecular Biology
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2013-10
DC.identifier	https://doi.org/10.1074/jbc.M113.498857
DC.description	This research was originally published in the Journal of Biological Chemistry. P. Patrizia Mangione, Gennaro Esposito, Annalisa Relini, Sara Raimondi, Riccardo Porcari, Sofia Giorgetti, Alessandra Corazza, Federico Fogolari, Amanda Penco, Yuji Goto, Young-Ho Lee, Hisashi Yagi, Ciro Cecconi, Mohsin M. Naqvi, Julian D. Gillmore, Philip N. Hawkins, Fabrizio Chiti, Ranieri Rolandi, Graham W. Taylor, Mark B. Pepys, Monica Stoppini and Vittorio Bellotti. Structure, Folding Dynamics, and Amyloidogenesis of D76N β2-Microglobulin: ROLES OF SHEAR FLOW, HYDROPHOBIC SURFACES, AND α-CRYSTALLIN. J. Biol. Chem. 2013; 288, 30917–30930. © the American Society for Biochemistry and Molecular Biology
DCTERMS.abstract	Systemic amyloidosis is a fatal disease caused by misfolding of native globular proteins, which then aggregate extracellularly as insoluble fibrils, damaging the structure and function of affected organs. The formation of amyloid fibrils in vivo is poorly understood. We recently identified the first naturally occurring structural variant, D76N, of human β2-microglobulin (β2m), the ubiquitous light chain of class I major histocompatibility antigens, as the amyloid fibril protein in a family with a new phenotype of late onset fatal hereditary systemic amyloidosis. Here we show that, uniquely, D76N β2m readily forms amyloid fibrils in vitro under physiological extracellular conditions. The globular native fold transition to the fibrillar state is primed by exposure to a hydrophobic-hydrophilic interface under physiological intensity shear flow. Wild type β2m is recruited by the variant into amyloid fibrils in vitro but is absent from amyloid deposited in vivo. This may be because, as we show here, such recruitment is inhibited by chaperone activity. Our results suggest general mechanistic principles of in vivo amyloid fibrillogenesis by globular proteins, a previously obscure process. Elucidation of this crucial causative event in clinical amyloidosis should also help to explain the hitherto mysterious timing and location of amyloid deposition.
DC.format	71279
citation_title	Structure, Folding Dynamics, and Amyloidogenesis of D76N β2-Microglobulin : ROLES OF SHEAR FLOW, HYDROPHOBIC SURFACES, AND α-CRYSTALLIN
citation_author	Mangione, P. Patrizia
	Esposito, Gennaro
	Relini, Annalisa
	Raimondi, Sara
	Porcari, Riccardo
	Giorgetti, Sofia
	Corazza, Alessandra
	Fogolari, Federico
	Penco, Amanda
	Goto, Yuji
	Lee, Young-Ho
	Yagi, Hisashi
	Cecconi, Ciro
	Naqvi, Mohsin M.
	Gillmore, Julian D.
	Hawkins, Philip N.
	Chiti, Fabrizio
	Rolandi, Ranieri
	Taylor, Graham W.
	Pepys, Mark B.
	Stoppini, Monica
	Bellotti, Vittorio
citation_publisher	American Society for Biochemistry and Molecular Biology
citation_language	English
citation_date	2013-10
citation_journal_title	Journal of Biological Chemistry
citation_volume	288
citation_issue	43
citation_firstpage	30917
citation_lastpage	30930
citation_doi	https://doi.org/10.1074/jbc.M113.498857
citation_public_url	https://hdl.handle.net/11094/71279

Structure, Folding Dynamics, and Amyloidogenesis of D76N β2-Microglobulin : ROLES OF SHEAR FLOW, HYDROPHOBIC SURFACES, AND α-CRYSTALLIN

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