title: Structure of an early native-like intermediate of β2-microglobulin amyloidogenesis.
abstract: To investigate early intermediates of β2-microglobulin (β2m) amyloidogenesis, we solved the structure of β2m containing the amyloidogenic Pro32Gly mutation by X-ray crystallography. One nanobody (Nb24) that efficiently blocks fibril elongation was used as a chaperone to co-crystallize the Pro32Gly β2m monomer under physiological conditions. The complex of P32G β2m with Nb24 reveals a trans peptide bond at position 32 of this amyloidogenic variant, whereas Pro32 adopts the cis conformation in the wild-type monomer, indicating that the cis to trans isomerization at Pro32 plays a critical role in the early onset of β2m amyloid formation.
authors.affiliation: Structural Biology Research Centre, VIB, Pleinlaan 2, 1050, Brussel, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussel, Belgium.
authors.forename: Saskia
authors.initials: S
authors.lastname: Vanderhaegen
authors.forename: Marcus
authors.initials: M
authors.lastname: Fislage
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Domanska
authors.forename: Wim
authors.initials: W
authors.lastname: Versées
authors.forename: Els
authors.initials: E
authors.lastname: Pardon
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
authors.forename: Jan
authors.initials: J
authors.lastname: Steyaert
mesh_terms: D020816:Amino Acid Motifs; D002942:Circular Dichroism; D018360:Crystallography, X-Ray / Q000379:methods; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005998:Glycine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D011392:Proline / Q000737:chemistry / Q000235:genetics; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D061905:Single-Domain Antibodies / Q000737:chemistry; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000235:genetics*
chemical_list: D061905:Single-Domain Antibodies; D001613:beta 2-Microglobulin; D011392:Proline; D005998:Glycine
keywords: X-ray crystallography; dialysis-related amyloidosis; nanobodies; proline isomerization; protein conformation; β2-microglobulin
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