Assembly assay identifies a critical region of human fibrillin-1 required for 10 - 12 nm diameter microfibril biogenesis

Jensen, Sacha A., Atwa, Ondine, and Handford, Penny A. (2021) Assembly assay identifies a critical region of human fibrillin-1 required for 10 - 12 nm diameter microfibril biogenesis. PLoS ONE, 16 (3). e0248532.

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Abstract

The human FBN1 gene encodes fibrillin-1 (FBN1); the main component of the 10 - 12 nm diameter extracellular matrix microfibrils. Marfan syndrome (MFS) is a common inherited connective tissue disorder, caused by FBN1 mutations. It features a wide spectrum of disease severity, from mild cases to the lethal neonatal form (nMFS), that is yet to be explained at the molecular level. Mutations associated with nMFS generally affect a region of FBN1 between domains TB3-cbEGF18 — the "neonatal region". To gain insight into the process of fibril assembly and increase our understanding of the mechanisms determining disease severity in MFS, we compared the secretion and assembly properties of FBN1 variants containing nMFS-associated substitutions with variants associated with milder, classical MFS (cMFS). In the majority of cases, both nMFS- and cMFS-associated neonatal region variants were secreted at levels comparable to wild type. Microfibril incorporation by the nMFS variants was greatly reduced or absent compared to the cMFS forms, however, suggesting that nMFS substitutions disrupt a previously undefined site of microfibril assembly. Additional analysis of a domain deletion variant caused by exon skipping also indicates that register in the neonatal region is likely to be critical for assembly. These data demonstrate for the first time new requirements for microfibril biogenesis and identify at least two distinct molecular mechanisms associated with disease substitutions in the TB3-cbEGF18 region; incorporation of mutant FBN1 into microfibrils changing their integral properties (cMFS) or the blocking of wild type FBN1 assembly by mutant molecules that prevents late-stage lateral assembly (nMFS).

Item ID: 67499
Item Type: Article (Research - C1)
ISSN: 1932-6203
Keywords: Marfan syndrome, microfibril, fibrillin, extracellular matrix, neonatal Marfan syndrome
Copyright Information: © 2021 Jensenet al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funders: Arthritis Research UK (AR), Medical Research Council (MRC)
Projects and Grants: AR project grant no. 20785, MRC grant number MR/M009831/1
Date Deposited: 16 Jun 2021 01:54
FoR Codes: 31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310105 Cellular interactions (incl. adhesion, matrix, cell wall) @ 50%
31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310108 Protein trafficking @ 25%
31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310199 Biochemistry and cell biology not elsewhere classified @ 25%
SEO Codes: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280102 Expanding knowledge in the biological sciences @ 50%
28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280103 Expanding knowledge in the biomedical and clinical sciences @ 50%
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