Fibulin-5 interacts with fibrillin-1 molecules and microfibrils

Freeman, Lyle J.; Lomas, Amanda; Hodson, Nigel; Sherratt, Michael J.; Mellody, Kieran T.; Weiss, Anthony S.; Shuttleworth, Adrian; Kielty, Cay M.

doi:10.1042/bj20050368

Cited by 94 publications

(100 citation statements)

References 28 publications

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“…While fibulin-2 and -4 are present at the interface between the central elastin core and its surrounding fibrillin microfibrils (8,18), fibulin-1 is located within the elastin core and fibulin-5 is associated with fibrillin microfibrils (8,19). Consistent with these observations, in vitro protein binding studies have shown that all fibulins are capable of binding to tropoelastin, albeit with different affinities (8,20,27), and that fibulin-2, -4, and -5 interact with the N-terminal region of fibrillin-1 (5,6,18).…”

supporting

confidence: 63%

Fibulin-2 Is Dispensable for Mouse Development and Elastic Fiber Formation

Sicot¹,

Tsuda²,

Markova³

et al. 2008

Molecular and Cellular Biology

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Fibulin-2 is an extracellular matrix protein belonging to the five-member fibulin family, of which two members have been shown to play essential roles in elastic fiber formation during development. Fibulin-2 interacts with two major constituents of elastic fibers, tropoelastin and fibrillin-1, in vitro and localizes to elastic fibers in many tissues in vivo. The protein is prominently expressed during morphogenesis of the heart and aortic arch vessels and at early stages of cartilage development. To examine its role in vivo, we generated mice that do not express the fibulin-2 gene (Fbln2) through homologous recombination of embryonic stem cells. Unexpectedly, the fibulin-2-null mice were viable and fertile and did not display gross and anatomical abnormalities. Histological and ultrastructural analyses revealed that elastic fibers assembled normally in the absence of fibulin-2. No compensatory up-regulation of mRNAs for other fibulin members was detected in the aorta and skin tissue. However, in the fibulin-2 null aortae, fibulin-1 immunostaining was increased in the inner elastic lamina, where fibulin-2 preferentially localizes. The results demonstrate that fibulin-2 is not required for mouse development and elastic fiber formation and suggest possible functional redundancy between fibulin-1 and fibulin-2.

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supporting

confidence: 63%

Fibulin-2 Is Dispensable for Mouse Development and Elastic Fiber Formation

Sicot¹,

Tsuda²,

Markova³

et al. 2008

Molecular and Cellular Biology

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“…Empty vector or adenovirus encoding ␤-galactosidase (␤-Gal) was used as a negative control. For high-titer injection, viruses were propagated on 911 cells and purified using discontinuous cesium chloride gradients as previously described (10). A total of 50 l of PBS containing adenovirus was subcutaneously injected into three midline injection points in the dorsal skin of P2 pups.…”

Section: Mice Fbln5mentioning

confidence: 99%

Molecular Analysis of Fibulin-5 Function during De Novo Synthesis of Elastic Fibers

Zheng¹,

Davis

Richardson³

et al. 2007

Molecular and Cellular Biology

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Elastic fibers contribute to the structural support of tissues and to the regulation of cellular behavior. Mice deficient for the fibulin-5 gene (fbln5 ؊/؊ ) were used to further elucidate the molecular mechanism of elastic fiber assembly. Major elastic fiber components were present in the skin of fbln5 ؊/؊ mice despite a dramatic reduction of mature elastic fibers. We found that fibulin-5 preferentially bound the monomeric form of elastin through N-terminal and C-terminal elastin-binding regions and to a preexisting matrix scaffold through calcium-binding epidermal growth factor (EGF)-like (CB-EGF) domains. We further showed that adenovirusmediated gene transfer of fbln5 was sufficient to regenerate elastic fibers and increase elastic fiber-cell connections in vivo. A mutant fibulin-5 lacking the first 28 amino acids of the first CB-EGF domain, however, was unable to rescue elastic fiber defects. Fibulin-5 thus serves as an adaptor molecule between monomeric elastin and the matrix scaffold to aid in elastic fiber assembly. These results also support the potential use of fibulin-5 as a therapeutic agent for the treatment of elastinopathies.

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“…Additional evidence for a close functional relationship of fibulins with components of the microfibril/elastic fiber system comes from in vitro protein-protein interaction studies. It has been demonstrated that fibulin-1, -2, -4, and -5 can interact with tropoelastin (30,33,36,37). In addition, fibulin-2 and -5 were shown to interact with fibrillin-1, and the binding epitopes were mapped to a relatively large N-terminal region of fibrillin-1 (31,37).…”

mentioning

confidence: 98%

Fibrillin-1 Interactions with Fibulins Depend on the First Hybrid Domain and Provide an Adaptor Function to Tropoelastin

El-Hallous

Sasaki

Hubmacher³

et al. 2007

Journal of Biological Chemistry

103

108

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Fibrillin-containing microfibrils in elastic and nonelastic extracellular matrices play important structural and functional roles in various tissues, including blood vessels, lung, skin, and bone. Microfibrils are supramolecular aggregates of several protein and nonprotein components. Recently, a large region in the N-terminal portion of fibrillin-1 was characterized as a multifunctional protein interaction site, including binding sites for fibulin-2 and -5 among others. Using a panel of recombinant fibrillin-1 swapped domain and deletion fragments, we demonstrate here that the conserved first hybrid domain in fibrillin-1 is essential for binding to fibulin-2, -4, and -5. Fibulin-3 and various isoforms of fibulin-1 did not interact with fibrillin-1. Although the first hybrid domain in fibrillin-1 is located in close vicinity to the self-assembly epitope, binding of fibulin-2, -4, and -5 did not interfere with self-assembly. However, these fibulins can associate with microfibrils at various levels of maturity. Formation of ternary complexes between fibrillin-1, fibulins, and tropoelastin demonstrated that fibulin-2 and -5 but much less fibulin-4, are able to act as molecular adaptors between fibrillin-1 and tropoelastin.The microfibril/elastic fiber system provides tissues, such as lung, blood vessels, and skin, with elastic properties. Microfibrils with a diameter of 10 -12 nm are typically located on the outer surface of elastic fibers and are thought to play an essential role in elastogenesis (1). Whereas elastic fibers are always associated with microfibrils, microfibrils themselves can occur in the absence of elastin in certain tissues such as ocular ciliary zonules, the kidney, or in close proximity to various basement membranes. The microfibril/elastic fiber system is a multicomponent assembly in the extracellular matrix, and for both, the microfibrils and the elastic fibers, a number of constituents have been described (for a review, see Ref 2). For most of the associated molecules, the exact relationship in terms of physical interaction with microfibrils and/or elastic fibers, and their functional relevance is not clear.The best described components of the microfibrils are a family of proteins consisting of three highly homologous members, fibrillin-1, -2, and -3 (3-9). Fibrillins, like many other extracellular glycoproteins, are characterized by a number of tandemly arranged domains. The most prominent domain is an epidermal growth factor-like domain (EGF), 2 which occurs 46 -47 times in fibrillins. These domains are stabilized by three intramolecular disulfide bonds, and the majority (42-43 domains) contain a consensus sequence for calcium binding (cbEGF) (10 -12). The tandemly arranged EGF and cbEGF domains are interspersed by two other types of domains, the transforming growth factor ␤-binding protein (TB) or 8-Cys domains and the hybrid domains. The seven TB/8-Cys domains are characterized by four intramolecular disulfide bonds, and a similar arrangement is predicted for the two hybrid domains, alth...

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Fibulin-5 interacts with fibrillin-1 molecules and microfibrils

Cited by 94 publications

References 28 publications

Fibulin-2 Is Dispensable for Mouse Development and Elastic Fiber Formation

Fibulin-2 Is Dispensable for Mouse Development and Elastic Fiber Formation

Molecular Analysis of Fibulin-5 Function during De Novo Synthesis of Elastic Fibers

Fibrillin-1 Interactions with Fibulins Depend on the First Hybrid Domain and Provide an Adaptor Function to Tropoelastin

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