Evidence for the Intramolecular Pleating Model of Fibrillin Microfibril Organisation from Single Particle Image Analysis

Lu, Yinhui; Holmes, David; Baldock, Clair

doi:10.1016/j.jmb.2005.03.066

Cited by 19 publications

(23 citation statements)

References 41 publications

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“…The currently accepted model of microfibril organization, the intramolecular pleating model (16,17), is depicted in Fig. 11D.…”

Section: Discussionmentioning

confidence: 99%

“…Based upon the length (ϳ150 nm) of the fibrillin monomer (4), the periodicity of fibrillin immunolocalization in tissue microfibrils (ϳ50 nm) (3), and the variable periodicities of unstretched and stretched extracted microfibrils (2), long fibrillin molecules were required to be compressed within the microfibril, if fibrillin molecules are unstaggered (3). However, because fibrillin molecules are composed of long tandemly repeated calciumbinding epidermal growth factor-like (cbEGF) 4 domain modules, whose structures are predicted to be rather rigidly linear, compression of fibrillin molecules within microfibrils was predicted to be unlikely, and so staggered models were preferred (12, 15).The prevailing model of fibrillin fibril organization is called the intramolecular pleating model, and it is based on best fitting fibrillin molecules to microfibril structure as determined by high resolution electron microscopic approaches (16,17). Details of the structure of microfibrils, revealed by automated electron tomography, were used to support a complex model of microfibril extensibility and elasticity.…”

mentioning

confidence: 99%

“…The prevailing model of fibrillin fibril organization is called the intramolecular pleating model, and it is based on best fitting fibrillin molecules to microfibril structure as determined by high resolution electron microscopic approaches (16,17). Details of the structure of microfibrils, revealed by automated electron tomography, were used to support a complex model of microfibril extensibility and elasticity.…”

mentioning

confidence: 99%

“…An initial head-to-tail alignment of fibrillin monomers, followed by several different folding events at the N-and C-terminal ends of the monomers, was proposed to result in microfibrils with fibrillin monomers arranged in parallel and one-third staggered (16). Various other staggered models of fibrillin molecules do not appear to fit the images of microfibrils as well as the intramolecular pleating model does (17). Difficulties with these attempts to fit fibrillin molecules to microfibril ultrastructure have been related primarily to the unknown contributions of other microfibril components.…”

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confidence: 99%

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Effects of Fibrillin-1 Degradation on Microfibril Ultrastructure

Kuo

Isogai

Keene

et al. 2007

Journal of Biological Chemistry

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Current models of the elastic properties and structural organization of fibrillin-containing microfibrils are based primarily on microscopic analyses of microfibrils liberated from connective tissues after digestion with crude collagenase. Results presented here demonstrate that this digestion resulted in the cleavage of fibrillin-1 and loss of specific immunoreactive epitopes. The proline-rich region and regions near the second 8-cysteine domain in fibrillin-1 were easily cleaved by crude collagenase. Other sites that may also be cleaved during microfibril digestion and extraction were identified. In contrast to collagenase-digested microfibrils, guanidine-extracted microfibrils contained all fibrillin-1 epitopes recognized by available antibodies. The ultrastructure of guanidine-extracted microfibrils differed markedly from that of collagenase-digested microfibrils. Fibrillin-1 filaments splayed out, extending beyond the width of the periodic globular beads. Both guanidine-extracted and collagenase-digested microfibrils were subjected to extensive digestion by crude collagenase. Collagenase digestion of guanidine-extracted microfibrils removed the outer filaments, revealing a core structure. In contrast to microfibrils extracted from tissues, cell culture microfibrils could be digested into short units containing just a few beads. These data suggest that additional cross-links stabilize the long beaded microfibrils in tissues. Based on the microfibril morphologies observed after these experiments, on the crude collagenase cleavage sites identified in fibrillin-1, and on known antibody binding sites in fibrillin-1, a model is proposed in which fibrillin-1 molecules are staggered in microfibrils. This model further suggests that the N-terminal half of fibrillin-1 is asymmetrically exposed in the outer filaments, whereas the C-terminal half of fibrillin-1 is present in the interior of the microfibril.Microfibrils have been extracted from a variety of tissues and visualized by electron microscopy as distinctive beaded string structures (1, 2). The molecular composition of these structures is assumed to be complex. However, based upon immunolocalization of fibrillin to these structures (2, 3) and the shape of fibrillin monomers (4, 5), fibrillins are thought to be the major backbone components of these extracted microfibrils. Fibrillincontaining microfibrils are ubiquitous in the connective tissue space (6), providing architectural support as well as information essential for appropriate signaling during morphogenesis (7-9). In human disorders associated with fibrillins, the structural integrity of fibrillin microfibrils is required for the proper function of certain connective tissues (10). Therefore, determination of the organization of fibrillin molecules within the microfibril is important basic information.The organization of fibrillin molecules within microfibrils has been controversial. Both parallel (head-to-tail) (3, 4) and antiparallel (11) arrangements of fibrillin molecules within microfibrils have been...

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“…The currently accepted model of microfibril organization, the intramolecular pleating model (16,17), is depicted in Fig. 11D.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of Fibrillin-1 Degradation on Microfibril Ultrastructure

Kuo

Isogai

Keene

et al. 2007

Journal of Biological Chemistry

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“…Fibrillin microfibrils have a complex ultrastructure resembling ''beads-on-a-string,'' with an average periodicity of 57 nm and a diameter of 18 nm as revealed by electron microscopy (EM) (2,3). They have a widespread distribution in nonelastin and elastincontaining tissues, such as the ciliary zonules, blood vessels, lung, and skin, and they act as a lattice for elastin deposition during elastic fiber formation.…”

mentioning

confidence: 99%

Nanostructure of fibrillin-1 reveals compact conformation of EGF arrays and mechanism for extensibility

Baldock

Siegler²,

Bax

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Fibrillin-1 is a 330-kDa multidomain extracellular matrix protein that polymerizes to form 57-nm periodic microfibrils, which are essential for all tissue elasticity. Fibrillin-1 is a member of the calcium-binding EGF repeat family and has served as a prototype for structural analyses. Nevertheless, both the detailed structure of fibrillin-1 and its organization within microfibrils are poorly understood because of the complexity of the molecule and the resistance of EGF arrays to crystallization. Here, we have used small-angle x-ray scattering and light scattering to analyze the solution structure of human fibrillin-1 and to produce ab initio structures of overlapping fragments covering 90% of the molecule. Rather than exhibiting a uniform rod shape as current models predict, the scattering data revealed a nonlinear conformation of calcium-binding EGF arrays in solution. This finding has major implications for the structures of the many other EGF-containing extracellular matrix and membrane proteins. The scattering data also highlighted a very compact, globular region of the fibrillin-1 molecule, which contains the integrin and heparan sulfate-binding sites. This finding was confirmed by calculating a 3D reconstruction of this region using electron microscopy and single-particle image analysis. Together, these data have enabled the generation of an improved model for microfibril organization and a previously undescribed mechanism for microfibril extensibility.elastic fibers ͉ fibrillin microfibrils ͉ solution x-ray scattering

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A fibrous membrane suspends the multifocal lens in the eyes of lampreys and African lungfishes

Gustafsson

Ekström

Kröger

2010

Journal of Morphology

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The sharpness and thus information content of the retinal image in the eye depends on the optical quality of the lens and its accurate positioning in the eye. Multifocal lenses create well-focused color images and are present in the eyes of all vertebrate groups studied to date (mammals, reptiles including birds, amphibians, and ray-finned fishes) and occur even in lampreys, i.e., the most basal vertebrates with well-developed eyes. Results from photoretinoscopy obtained in this study indicate that the Dipnoi (lungfishes), i.e., the closest piscine relatives to tetrapods, also possess multifocal lenses. Suspension of the lens is complex and sophisticated in teleosts (bony fishes) and tetrapods. We studied lens suspension using light and electron microscopy in one species of lamprey (Lampetra fluviatilis) and two species of African lungfish (Protopterus aethiopicus aethiopicus and Protopterus annectens annectens). A fibrous and highly transparent membrane suspends the lens in both of these phylogenetically widely separated vertebrate groups. The membrane attaches to the lens approximately along the lens equator, from where it extends to the ora retinalis. The material forming the membrane is similar in ultrastructure to microfibrils in the zonule fibers of tetrapods. The membrane, possibly in conjunction with the cornea, iris, and vitreous body, seems suitable for keeping the lens in the correct position for well-focused imaging. Suspension of the lens by a multitude of zonule fibers in tetrapods may have evolved from a suspensory membrane similar to that in extant African lungfishes, a structure that seems to have appeared first in the lamprey-like ancestors of allextant vertebrates.

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Evidence for the Intramolecular Pleating Model of Fibrillin Microfibril Organisation from Single Particle Image Analysis

Cited by 19 publications

References 41 publications

Effects of Fibrillin-1 Degradation on Microfibril Ultrastructure

Effects of Fibrillin-1 Degradation on Microfibril Ultrastructure

Nanostructure of fibrillin-1 reveals compact conformation of EGF arrays and mechanism for extensibility

A fibrous membrane suspends the multifocal lens in the eyes of lampreys and African lungfishes

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