nemoci-sympt/METABOLISMUS/marfanuv-syndrom/fibrilin

FBN1 - gen kódující glykoprotein Fibrilin 1

• Gen pro fibrilin 1
• Gen na chromozomu 15

Synonyma a symboly pro fibrilin 1

• Fibrillin, fibrillin 15, FBN
• MASS, OCTD, WMS, ACMICD
• GPHYSD2; MFS1; SGS; SSKS; WMS2

Struktura firbilinu 1

Domény:

• Epidermal growth factor-like (EGF) domain [12]
• 8-Cys/TB domain [12]
• 3 and 4 stabilizing disulfide bonds
• calcium binding type domains [12]
• calcium binding EGF like domains (cbEGF)
• Calcium binding to cbEGF domains in fibrillins is essential for stabilization of a rod-like structure [12]
• For the resistance against proteases [12]
• For the interaction with ligands:
• Heparan sulfate [12]
• MAGP-1 [12]
• Fibulin-2 [12]

Složení fibrilinu 1

• Cca 14% cysteine [11]
• One-third appears to be in the free reactive sulfhydryl form [11]
• Majority of these cysteine residues are predicted to be involved in intramolecular disulfide bonds stabilizing individual domains [12]
• About 75% of the protein, are the 46 EGF-like repeats [11]
• Cysteine-rich domains
• Originally found in human epidermal growth factor [11]
• 43 of these repeats
• calcium binding
• May mediate protein-protein interactions
• Called calcium-binding EGF-like repeats (cbEGFs) [11]

Vazby fibrillinu-1

• Sequence of exons 44–49
• Regulates the bioavailability of endogenous TGF beta 1
• Stimulating Smad2 signaling [1]
• Release of TGF beta does not require intact cells, proteolysis, or changes in the expression of TGF beta or its receptors [1]
• Regulate TGF beta
• LLC + fibrillin-rich microfibrils
• Small fibrillin-1 fragments
• Greater ability to stimulate Smad2 signaling and TGF beta [1]
• TGFß may become activated during the release of LLC from microfibrils
• Conformational changes
• Fibrillin-1– and SLC-binding sites are within the same C-terminal region of LTBP-1 [1]
• Assembly into microfibrils
• Elastic fiber formation
• Interactions with glycosaminoglycans
• Heparin
• Four high affinity heparin-binding sites on fibrillin-1
• Heparin and MAGP-1 competed for binding to the fibrillin-1 N terminus
• Heparin and tropoelastin competed for binding to a central fibrillin-1 sequence
• Heparin can profoundly influence microfibril and elastic fiber assembly
• Heparin saccharides - analogous to S-domains of heparan sulfate
• With more than 12 monosaccharide units bound strongly to all four fibrillin-1 sites
• Hyaluronan and chondroitin sulfate
• Did not interact significantly with fibrillin-1 [2]

Funkce fibrilinu 1

• 1991 identifikován Francescem Ramirezem v New Yorku
• Synthetized as profibrillin-1, furin mediated, involved in the maintenance of elastic fibers and anchoring epithelial cells to the interstitial matrix [9]
• Secernován fibroblasty do extracelulární matrix

Mikrofibrily - uspořádání elastinu

• Structural component of 10-12 nm calcium-binding microfibrils [4] [9]
• In association with elastin or in elastin-free bundles [9]
• Scaffold for the deposition of elastin
• Correct formation of the elastic fibers [12]
• Fibrillin aggregation do mikrofibril
• Initiates early after biosynthesis of the molecules [11]
• N terminus of human FIB1 could assemble in a linear fashion with the C terminus of another FIB1 molecule to form homotypic FIB1 microfibrils in the presence of calcium [11]
• Tedy i pro tvorbu mikrofibril je potřeba vápník extracelulárně. Má na toto vliv podávání vápníku ? (Asi ne...toho je tam asi tak jako tak dost ?)
• The calcium concentration in extracellular environments is predicted to be about 1-2 mm [12]
• High affinity calcium binding sites
• Expected to be fully saturated [12]
• Low affinity binding sites
• Likely only partially saturated [12]
• Regulation of flexibility, elastic properties, degradation, and/or protein-protein interactions [12]
• Force bearing structural support in elastic and nonelastic connective tissue [4]
• Takže i v kostech... Mají častější zlomeniny?

• Fibrillin-1 deposition in the extracellular matrix
• Enhanced in transgenic mice overexpressing Adamtsl6-beta in cartilaginous tissues [11]
• ADAMTSL6 promotes the assembly of fibrillin-1 microfibrils [11]
• Asociované proteiny s fibrilinovými mikrofibrily
• Elastin
• Thrombospondin
• Microfibril-associated glycoprotein
• Emilin
• Fibrillin-2 [11]
• Anchoring the dermal elastic fibers in the extracellular matrix and to the lamina densa [13]

Vývoj tkání a jejich pojiv

• Heart development
• Skeletal system development [4]

Regulace růstových faktorů extracelulární matrix

• Váže Multiple Bone Morphogenetic Proteins (BMPs) [8]
• Váže Growth and Differentiation Factor-5 (GDF-5) [8]
• Attachment of LTBPs [8]
• Selectively binds the metalloproteinase ADAMTS-10 [8]
• Binds some non-enzymatic ADAMTSL proteins [8]
• Two distinct regions bound to ADAMTS10, one in the N-terminal half and another in the C-terminal half [10]
• Enabling a clustering of these protein complexes in the vicinity of the fibrillin-1 RGD site
• Potential for integrin involvement in ADAMTS/ADAMTSL/fibrillin functions [8]

• Sequestering (váže - blokuje funkci / uvolňuje) of TGF beta in extracellular matrix
• Extracellular control of growth factor signaling [5]
• Regulation of dermal collagen production [5]
• Fibrillin-1 microfibrils - large latent TGF beta complex (LLC) [8]
• Seven transforming growth factor beta 1-binding protein-like domains (LTBP) [10]
• Regulace růstu a diferenciace buněk [1]
• Osteoblast maturation [9]
• By controlling TGF-beta bioavailability [9]

• Colocalizing with FBNL2 in skin, perichondrium [9]
• With FBN2, regulate lung fibroblast migration [10]

Metaloproteinázy

• Up-regulating MMP1 and MMP3 through the RGD motif
• Role in the progressive breakdown of microfibrils [10]
• Role in the pathogenesis of Marfan syndrome [10]
• Zlepšilo by stav něco, co umí potlačit aktivitu metaloproteinázy 1 a 3 ?

Mechanický senzor

• Extended fibrillin fibril may function as a sensor for mechanical distortion of the matrix
• Signaling the cell a need for additional, reinforcing structural components like collagens [8]
• Zlepší se stav dodáním kolagenu v doplňcích ?
• "presence of large latent TGF beta complexes within the fibrillin microenvironment conveniently couples matrix mechanics with available signals for upregulation of collagens" [8]
• "Installation of new structural materials into pre-existing matrices likely requires remodeling enzymes like metalloproteinases. ADAMTS enzymes, localized to the fibrillin microenvironment as well, possibly with the help of ADAMTSL proteins, could serve such purposes, or they might participate in the activation of nearby latent growth factors". [8]

Tkáňová exprese:

• In basement membrane
• In proteinaceous extracellular matrix [4]
• In the connective tissue matrices of skin, lung, kidney, vasculature, cartilage, tendon, muscle, cornea, and ciliary zonule [11]

Literatura: