1uzj is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
FBN1_HUMAN Defects in FBN1 are a cause of Marfan syndrome (MFS) [MIM:154700. MFS is an autosomal dominant disorder that affects the skeletal, ocular, and cardiovascular systems. A wide variety of skeletal abnormalities occurs with MFS, including scoliosis, chest wall deformity, tall stature, abnormal joint mobility. Ectopia lentis occurs in up to about 80% of MFS patients and is almost always bilateral. The leading cause of premature death in MFS patients is progressive dilation of the aortic root and ascending aorta, causing aortic incompetence and dissection. Note=The majority of the more than 600 mutations in FBN1 currently known are point mutations, the rest are frameshifts and splice site mutations. Marfan syndrome has been suggested in at least 2 historical figures, Abraham Lincoln and Paganini.[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] Defects in FBN1 are a cause of ectopia lentis, isolated, autosomal dominant (ECTOL1) [MIM:129600. An ocular abnormality characterized by partial or complete displacement of the lens from its space resulting from defective zonule formation.[34][35][36][37] Defects in FBN1 are the cause of Weill-Marchesani syndrome 2 (WMS2) [MIM:608328. A rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and eye abnormalities including microspherophakia, ectopia lentis, severe myopia and glaucoma.[38] Defects in FBN1 are a cause of Shprintzen-Goldberg craniosynostosis syndrome (SGS) [MIM:182212. SGS is a very rare syndrome characterized by a marfanoid habitus, craniosynostosis, characteristic dysmorphic facial features, skeletal and cardiovascular abnormalities, mental retardation, developmental delay and learning disabilities.[:] Defects in FBN1 are a cause of overlap connective tissue disease (OCTD) [MIM:604308. A heritable disorder of connective tissue characterized by involvement of the mitral valve, aorta, skeleton, and skin. MASS syndrome is closely resembling both the Marfan syndrome and the Barlow syndrome. However, no dislocation of the lenses or aneurysmal changes occur in the aorta, and the mitral valve prolapse is by no means invariable.[39] Defects in FBN1 are a cause of stiff skin syndrome (SSKS) [MIM:184900. It is a syndrome characterized by hard, thick skin, usually over the entire body, which limits joint mobility and causes flexion contractures. Other occasional findings include lipodystrophy and muscle weakness.[40] Defects in FBN1 are the cause of geleophysic dysplasia type 2 (GPHYSD2) [MIM:614185. An autosomal dominant disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have characteristic facial features including a 'happy' face with full cheeks, shortened nose, hypertelorism, long and flat philtrum, and thin upper lip. Other distinctive features include progressive cardiac valvular thickening often leading to an early death, toe walking, tracheal stenosis, respiratory insufficiency, and lysosomal-like storage vacuoles in various tissues.[41] Defects in FBN1 are the cause of acromicric dysplasia (ACMICD) [MIM:102370. An autosomal dominant disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have distinct facial features, including round face, well-defined eyebrows, long eyelashes, bulbous nose with anteverted nostrils, long and prominent philtrum, and thick lips with a small mouth. Other characteristic features include hoarse voice and pseudomuscular build, and there are distinct skeletal features as well, including an internal notch of the femoral head, internal notch of the second metacarpal, and external notch of the fifth metacarpal.[42]
Function
FBN1_HUMAN Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles. Fibrillin-1-containing microfibrils provide long-term force bearing structural support. Regulates osteoblast maturation by controlling TGF-beta bioavailability and calibrating TGF-beta and BMP levels, respectively (By similarity).[43]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Human fibrillin-1, the major structural protein of extracellular matrix (ECM) 10-12 nm microfibrils, is dominated by 43 calcium binding epidermal growth factor-like (cbEGF) and 7 transforming growth factor beta binding protein-like (TB) domains. Crystal structures reveal the integrin binding cbEGF22-TB4-cbEGF23 fragment of human fibrillin-1 to be a Ca(2+)-rigidified tetragonal pyramid. We suggest that other cbEGF-TB pairs within the fibrillins may adopt a similar orientation to cbEGF22-TB4. In addition, we have located a flexible RGD integrin binding loop within TB4. Modeling, cell attachment and spreading assays, immunocytochemistry, and surface plasmon resonance indicate that cbEGF22 bound to TB4 is a requirement for integrin activation and provide insight into the molecular basis of the fibrillin-1 interaction with alphaVbeta3. In light of our data, we propose a novel model for the assembly of the fibrillin microfibril and a mechanism to explain its extensibility.
Structure of the integrin binding fragment from fibrillin-1 gives new insights into microfibril organization.,Lee SS, Knott V, Jovanovic J, Harlos K, Grimes JM, Choulier L, Mardon HJ, Stuart DI, Handford PA Structure. 2004 Apr;12(4):717-29. PMID:15062093[44]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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↑Loeys B, Nuytinck L, Delvaux I, De Bie S, De Paepe A. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001 Nov 12;161(20):2447-54. PMID:11700157
↑Katzke S, Booms P, Tiecke F, Palz M, Pletschacher A, Turkmen S, Neumann LM, Pregla R, Leitner C, Schramm C, Lorenz P, Hagemeier C, Fuchs J, Skovby F, Rosenberg T, Robinson PN. TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. Hum Mutat. 2002 Sep;20(3):197-208. PMID:12203992 doi:10.1002/humu.10112
↑Korkko J, Kaitila I, Lonnqvist L, Peltonen L, Ala-Kokko L. Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions. J Med Genet. 2002 Jan;39(1):34-41. PMID:11826022
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↑Loeys B, Nuytinck L, Delvaux I, De Bie S, De Paepe A. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001 Nov 12;161(20):2447-54. PMID:11700157
↑Katzke S, Booms P, Tiecke F, Palz M, Pletschacher A, Turkmen S, Neumann LM, Pregla R, Leitner C, Schramm C, Lorenz P, Hagemeier C, Fuchs J, Skovby F, Rosenberg T, Robinson PN. TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. Hum Mutat. 2002 Sep;20(3):197-208. PMID:12203992 doi:10.1002/humu.10112
↑Korkko J, Kaitila I, Lonnqvist L, Peltonen L, Ala-Kokko L. Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions. J Med Genet. 2002 Jan;39(1):34-41. PMID:11826022
↑Lonnqvist L, Child A, Kainulainen K, Davidson R, Puhakka L, Peltonen L. A novel mutation of the fibrillin gene causing ectopia lentis. Genomics. 1994 Feb;19(3):573-6. PMID:8188302 doi:https://dx.doi.org/S0888-7543(84)71110-4
↑Faivre L, Gorlin RJ, Wirtz MK, Godfrey M, Dagoneau N, Samples JR, Le Merrer M, Collod-Beroud G, Boileau C, Munnich A, Cormier-Daire V. In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet. 2003 Jan;40(1):34-6. PMID:12525539
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↑Le Goff C, Mahaut C, Wang LW, Allali S, Abhyankar A, Jensen S, Zylberberg L, Collod-Beroud G, Bonnet D, Alanay Y, Brady AF, Cordier MP, Devriendt K, Genevieve D, Kiper PO, Kitoh H, Krakow D, Lynch SA, Le Merrer M, Megarbane A, Mortier G, Odent S, Polak M, Rohrbach M, Sillence D, Stolte-Dijkstra I, Superti-Furga A, Rimoin DL, Topouchian V, Unger S, Zabel B, Bole-Feysot C, Nitschke P, Handford P, Casanova JL, Boileau C, Apte SS, Munnich A, Cormier-Daire V. Mutations in the TGFbeta binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am J Hum Genet. 2011 Jul 15;89(1):7-14. doi: 10.1016/j.ajhg.2011.05.012. Epub, 2011 Jun 16. PMID:21683322 doi:10.1016/j.ajhg.2011.05.012
↑Le Goff C, Mahaut C, Wang LW, Allali S, Abhyankar A, Jensen S, Zylberberg L, Collod-Beroud G, Bonnet D, Alanay Y, Brady AF, Cordier MP, Devriendt K, Genevieve D, Kiper PO, Kitoh H, Krakow D, Lynch SA, Le Merrer M, Megarbane A, Mortier G, Odent S, Polak M, Rohrbach M, Sillence D, Stolte-Dijkstra I, Superti-Furga A, Rimoin DL, Topouchian V, Unger S, Zabel B, Bole-Feysot C, Nitschke P, Handford P, Casanova JL, Boileau C, Apte SS, Munnich A, Cormier-Daire V. Mutations in the TGFbeta binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am J Hum Genet. 2011 Jul 15;89(1):7-14. doi: 10.1016/j.ajhg.2011.05.012. Epub, 2011 Jun 16. PMID:21683322 doi:10.1016/j.ajhg.2011.05.012
↑Lee SS, Knott V, Jovanovic J, Harlos K, Grimes JM, Choulier L, Mardon HJ, Stuart DI, Handford PA. Structure of the integrin binding fragment from fibrillin-1 gives new insights into microfibril organization. Structure. 2004 Apr;12(4):717-29. PMID:15062093 doi:10.1016/j.str.2004.02.023
↑Lee SS, Knott V, Jovanovic J, Harlos K, Grimes JM, Choulier L, Mardon HJ, Stuart DI, Handford PA. Structure of the integrin binding fragment from fibrillin-1 gives new insights into microfibril organization. Structure. 2004 Apr;12(4):717-29. PMID:15062093 doi:10.1016/j.str.2004.02.023
