Structural and compositional diversity of fibrillin microfibrils in human tissues

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Elastic fibres comprising fibrillin microfibrils and elastin are present in many tissues, including the skin, lung, and arteries where they confer elasticity and resilience. Although fibrillin microfibrils play distinct and tissue-specific functional roles, it is unclear whether their ultrastructure and composition differ between elastin-rich (skin) and elastin-poor (ciliary body and zonule) organs or after in vitro synthesis by cultured cells. Here, we used atomic force microscopy, which revealed that the bead morphology of fibrillin microfibrils isolated from the human eye differs from those isolated from the skin. Using newly developed pre-MS preparation methods and LC-MS/MS, we detected tissue-specific regions of the fibrillin-1 primary structure that were differentially susceptible to proteolytic extraction. Comparing tissue- and culture-derived microfibrils, we found that dermis- and dermal fibroblast-derived fibrillin microfibrils differ in both bead morphology and periodicity and also exhibit regional differences in fibrillin-1 proteolytic susceptibility. In contrast, collagen VI microfibrils from the same dermal or fibroblast samples were invariant in ultrastructure (periodicity) and protease susceptibility. Finally, we observed that skin- and eye-derived microfibril suspensions were enriched in elastic fibre- and basement membrane-associated proteins, respectively. LC-MS/MS also identified proteins (such as calreticulin and protein disulphide isomerase) that are potentially fundamental to fibrillin microfibril biology, regardless of their tissue source. Fibrillin microfibrils synthesised in cell culture lacked some of these key proteins (MFAPs 2 and 4 and fibrillin-2). These results showcase the structural diversity of these key extracellular matrix assemblies, which may relate to their distinct roles in the tissues where they reside.

Bibliographical metadata

Original languageEnglish
Pages (from-to)5117-5133
Number of pages17
JournalThe Journal of biological chemistry
Issue number14
Early online date16 Feb 2018
Publication statusPublished - 6 Apr 2018

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