Fibrillin

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Fibrillin-1
Fibrillin-1
Ribbon model of fibrillin-1, according to PDB  2W86

Existing structural data: 2W86

Properties of human protein
Identifier
Gene names FBN1; FBN, MFS1, WMS
External IDs

Fibrillin-2
Properties of human protein
Identifier
Gene names FBN2; CCA
External IDs

Fibrillin-3
Properties of human protein
Identifier
Gene name FBN3
External IDs

Fibrillin is a glycoprotein that is essential for the formation of elastic fibers and is found in connective tissue . Fibrillin is secreted into the extracellular matrix by fibroblasts . They create microfibrils that serve as a framework for the storage of elastin .

properties

Controlling the bioavailability of the growth factor TGF-β is important for tissue formation and homeostasis . The deposition of the latent TGF-β complex (LLC) in the extracellular matrix is ​​caused by fibrillin microfibrils. The protein LTBP-1 (Latent TGFβ-binding protein 1) in the complex interacts with fibronectin during fibrillogenesis. In addition, fibrillins participate in the structural maintenance of the extracellular matrix by binding to BMP7- like growth factors.

Clinical significance

Mutations in FBN1 and FBN2 are related to scoliosis .

species

Fibrillin-1

Fibrillin-1 is the main component of the microfibrils which, in the case of elastic fibers, surround the amorphous elastin core like a sheath. Four forms of fibrillins have been described so far. Fibrillin-1 was isolated by Engvall in 1986, and mutations in the FBN1 gene are responsible for Marfan's syndrome .

The protein is found in humans and its gene is on chromosome 15 . To date, more than 1500 different mutations have been described.

Structure
So far there is no complete, high-resolution structure of fibrillin-1. However, shorter fragments were produced recombinantly and their structures were elucidated with X-ray crystallography or NMR spectroscopy . A more recent example is the structure of the fibrillin-1 hybrid domain in relation to the calcium-binding epidermal growth factor domain. This was determined by means of X-ray crystallography and a resolution of 1.8 Å. The microfibils, which consist of fibrillin proteins, are important for different interactions between cells and the extracellular matrix .

Fibrillin-2

Fibrillin-2 was first isolated by Zhang in 1994. It is believed that it plays an essential role in the early phase of elastogenesis (formation of elastic fibers). Mutations in the fibrillin-2 gene have been linked to Beals-Hecht syndrome .

Fibrillin-3

Fibrillin-3 is believed to be primarily found in the brain. It has also been shown for the field mouse that fibrillin-3 is found in the ovaries and in the gonad.

Fibrillin-4

Fibrillin-4 was first discovered in the zebrafish , its sequence is very similar to that of fibillin-2.

Individual evidence

  1. ^ CM Kielty, C. Baldock, D. Lee, MJ Rock, JL Ashworth, CA Shuttleworth: Fibrillin: from microfibril assembly to biomechanical function. In: Philosophical Transactions of the Royal Society B: Biological Sciences . tape 357 , no. 1418 , 2002, ISSN  0962-8436 , p. 207–217 , doi : 10.1098 / rstb.2001.1029 , PMID 11911778 , PMC 1692929 (free full text).
  2. ↑ Inderbir Singh: Textbook of human histology . 5th edition. Jaypee Brothers, New Delhi 2006, ISBN 81-8061-809-9 , pp. 64 ff .
  3. ^ T. Massam-Wu, M. Chiu, R. Choudhury, SS Chaudhry, AK Baldwin, A. McGovern, C. Baldock, CA Shuttleworth, CM Kielty: Assembly of fibrillin microfibrils governs extracellular deposition of latent TGFβ . In: Journal of Cell Science . tape 123 , no. 17 , 2010, ISSN  0021-9533 , p. 3006-3018 , doi : 10.1242 / jcs.073437 , PMID 20699357 .
  4. ^ Ian Robertson, Sacha Jensen, Penny Handford: TB domain proteins: evolutionary insights into the multifaceted roles of fibrillins and LTBPs . In: Biochemical Journal . tape 433 , no. 2 , 2011, ISSN  0264-6021 , p. 263-276 , doi : 10.1042 / BJ20101320 , PMID 21175431 ( biochemj.org ).
  5. ↑ JG Buchan, DM Alvarado, GE Haller, C Cruchaga, MB Harms, T Zhang, MC Willing, DK Grange, AC Braverman, NH Miller, JA Morcuende, NL Tang, TP Lam, BK Ng, JC Cheng, MB Dobbs, CA Gurnett: Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis . In: Human Molecular Genetics . tape 23 , no. 19 , 2014, ISSN  1460-2083 , p. 5271-5282 , doi : 10.1093 / hmg / ddu224 , PMID 24833718 , PMC 4159151 (free full text).
  6. ↑ LY Sakai: Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils . In: The Journal of Cell Biology . tape 103 , no. 6 , December 1986, ISSN  0021-9525 , pp. 2499-2509 , PMID 3536967 , PMC 2114568 (free full text).
  7. ^ Alan E. Guttmacher, Harry C. Dietz: New therapeutic approaches to mendelian disorders . In: The New England Journal of Medicine . tape 363 , no. 9 , August 2010, ISSN  1533-4406 , p. 852-863 , doi : 10.1056 / NEJMra0907180 , PMID 20818846 .
  8. ↑ Y. of Kodolitsch: Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome . In: The Application of Clinical Genetics . tape 8 , 2015, ISSN  1178-704X , p. 137–155 , doi : 10.2147 / TACG.S60472 , PMID 26124674 , PMC 4476478 (free full text).
  9. ↑ H. Zhang, SD Apfelroth, W. Hu; EC Davis, C. Sanguineti, J. Bonadio, RP Mecham, F. Ramirez: Structure and expression of fibrillin-2, a novel microfibrillar component preferentially located in elastic matrices . In: The Journal of Cell Biology . tape 124 , no. 5 , 1994, ISSN  0021-9525 , pp. 855-863 , PMID 8120105 , PMC 2119952 (free full text).
  10. ↑ GM Corson, NL Charbonneau, DR Keene, LY Sakai: Differential expression of fibrillin-3 adds to microfibril variety in human and avian, but not rodent, connective tissues . In: Genomics . tape 83 , no. 3 , March 2004, ISSN  0888-7543 , p. 461-472 , doi : 10.1016 / j.ygeno.2003.08.023 , PMID 14962672 .
  11. ↑ John M. Gansner, Erik C. Madsen, Robert P. Mecham, Jonathan D. Gitlin: Essential role for fibrillin-2 in zebrafish notochord and vascular morphogenesis . In: Developmental Dynamics. An Official Publication of the American Association of Anatomists . tape 237 , no. October 10 , 2008, ISSN  1058-8388 , p. 2844-2861 , doi : 10.1002 / dvdy.21705 , PMID 18816837 , PMC 3081706 (free full text).