Fibrillin microfibril structure identifies long-range effects of inherited pathogenic mutations affecting a key regulatory latent TGFβ-binding site.
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
received:
14
12
2021
accepted:
28
02
2023
medline:
19
5
2023
pubmed:
21
4
2023
entrez:
20
04
2023
Statut:
ppublish
Résumé
Genetic mutations in fibrillin microfibrils cause serious inherited diseases, such as Marfan syndrome and Weill-Marchesani syndrome (WMS). These diseases typically show major dysregulation of tissue development and growth, particularly in skeletal long bones, but links between the mutations and the diseases are unknown. Here we describe a detailed structural analysis of native fibrillin microfibrils from mammalian tissue by cryogenic electron microscopy. The major bead region showed pseudo eightfold symmetry where the amino and carboxy termini reside. On the basis of this structure, we show that a WMS deletion mutation leads to the induction of a structural rearrangement that blocks interaction with latent TGFβ-binding protein-1 at a remote site. Separate deletion of this binding site resulted in the assembly of shorter fibrillin microfibrils with structural alterations. The integrin α
Identifiants
pubmed: 37081316
doi: 10.1038/s41594-023-00950-8
pii: 10.1038/s41594-023-00950-8
pmc: PMC10191836
doi:
Substances chimiques
Fibrillins
0
Transforming Growth Factor beta
0
Fibrillin-1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
608-618Subventions
Organisme : Wellcome Trust
ID : 108466/Z/15/Z
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/T017643/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S015779/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203128/Z/16/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2023. The Author(s).
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