Structure and Interdomain Interactions of a Hybrid Domain: A Disulphide-Rich Module of the Fibrillin/LTBP Superfamily of Matrix Proteins

Jensen, Sacha A.; Iqbal, Saba; Lowe, E.D.; Redfield, Christina; Handford, Penny A.

doi:10.1016/j.str.2009.03.014

Cited by 43 publications

(56 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Structural studies of relevant fibrillin-1 recombinant peptides have been performed (13,22). These studies do not, however, clarify whether the cryptic epitopes that we have identified are made cryptic by the structure of polymerized fibrillin.…”

Section: Discussionmentioning

confidence: 83%

“…Solution structures of recombinant peptides containing the second hybrid domain of fibrillin-1 indicated that this region may be V-shaped, with the hybrid domain forming the "V" (13), but a crystallographic analysis of the second hybrid domain and flanking regions suggested, instead, a near linear arrangement of these domains (22). Therefore, it is unclear from these studies whether cryptic epitopes near the second hybrid domain might be hidden by fibrillin tertiary structure.…”

Section: Discussionmentioning

confidence: 92%

See 1 more Smart Citation

Microfibril Structure Masks Fibrillin-2 in Postnatal Tissues

Charbonneau

Jordan

Keene

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Fibrillin microfibrils are polymeric structures present in connective tissues. The importance of fibrillin microfibrils to connective tissue function has been demonstrated by the multiple genetic disorders caused by mutations in fibrillins and in microfibril-associated molecules. However, knowledge of microfibril structure is limited, largely due to their insolubility. Most previous studies have focused on how fibrillin-1 is organized within microfibril polymers. In this study, an immunochemical approach was used to circumvent the insolubility of microfibrils to determine the role of fibrillin-2 in postnatal microfibril structure. Results obtained from studies of wild type and fibrillin-1 null tissues, using monoclonal and polyclonal antibodies with defined epitopes, demonstrated that N-terminal fibrillin-2 epitopes are masked in postnatal microfibrils and can be revealed by enzymatic digestion or by genetic ablation of Fbn1. From these studies, we conclude that fetal fibrillin polymers form an inner core within postnatal microfibrils and that microfibril structure evolves as growth and development proceed into the postnatal period. Furthermore, documentation of a novel cryptic site present in EGF4 in fibrillin-1 underscores the molecular complexity and tissue-specific differences in microfibril structure.

show abstract

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 92%

Microfibril Structure Masks Fibrillin-2 in Postnatal Tissues

Charbonneau

Jordan

Keene

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…When primary sequences of hybrid domains in fibrillins where first analyzed, it was noted that they combine sequence homology at their N-termini with TB domains and at their C-termini with EGF domains [7], [26]. More recently, a high resolution structure of the human hybrid 2 domain demonstrated that these similarities in the primary sequence are fully reflected in the three-dimensional structure of this domain, proving that the hybrid domain is indeed an evolutionary “hybrid” between TB and cbEGF domains [27].…”

Section: Resultsmentioning

confidence: 99%

The Evolution of Extracellular Fibrillins and Their Functional Domains

2012

View full text Add to dashboard Cite

Fibrillins constitute the major backbone of multifunctional microfibrils in elastic and non-elastic extracellular matrices, and are known to interact with several binding partners including tropoelastin and integrins. Here, we study the evolution of fibrillin proteins. Following sequence collection from 39 organisms representative of the major evolutionary groups, molecular evolutionary genetics and phylogeny inference software were used to generate a series of evolutionary trees using distance-based and maximum likelihood methods. The resulting trees support the concept of gene duplication as a means of generating the three vertebrate fibrillins. Beginning with a single fibrillin sequence found in invertebrates and jawless fish, a gene duplication event, which coincides with the appearance of elastin, led to the creation of two genes. One of the genes significantly evolved to become the gene for present-day fibrillin-1, while the other underwent evolutionary changes, including a second duplication, to produce present-day fibrillin-2 and fibrillin-3. Detailed analysis of several sequences and domains within the fibrillins reveals distinct similarities and differences across various species. The RGD integrin-binding site in TB4 of all fibrillins is conserved in cephalochordates and vertebrates, while the integrin-binding site within cbEGF18 of fibrillin-3 is a recent evolutionary change. The proline-rich domain in fibrillin-1, glycine-rich domain in fibrillin-2 and proline-/glycine-rich domain in fibrillin-3 are found in all analyzed tetrapod species, whereas it is completely replaced with an EGF-like domain in cnidarians, arthropods, molluscs and urochordates. All collected sequences contain the first 9-cysteine hybrid domain, and the second 8-cysteine hybrid domain with exception of arthropods containing an atypical 10-cysteine hybrid domain 2. Furin cleavage sites within the N- and C-terminal unique domains were found for all analyzed fibrillin sequences, indicating an essential role for processing of the fibrillin pro-proteins. The four cysteines in the unique N-terminus and the two cysteines in the unique C-terminus are also highly conserved.

show abstract

“…Hyb domains are found only twice in all mammalian fibrillins. They show similarities with TB domains in their N-terminal region and with cbEGF domains in their C-terminal region [9,26,27]. Other protein domains in fibrillin-1 include the unique N-and C-terminal domains, as well as a proline-rich domain close to the N-terminus.…”

Section: Fibrillin-1 Is a Multidomain Proteinmentioning

confidence: 93%