PDBsum entry 1lmj

Go to PDB code: 
protein metals links
Structural protein PDB id
Protein chain
86 a.a. *
_CA ×2
* Residue conservation analysis
PDB id:
Name: Structural protein
Title: Nmr study of the fibrillin-1 cbegf12-13 pair of ca2+ binding epidermal growth factor-like domains
Structure: Fibrillin 1. Chain: a. Fragment: cbegf12-13. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: fbn1. Expressed in: escherichia coli. Expression_system_taxid: 562.
NMR struc: 25 models
Authors: R.S.Smallridge,P.Whiteman,J.M.Werner,I.D.Campbell, P.A.Handford,A.K.Downing
Key ref:
R.S.Smallridge et al. (2003). Solution structure and dynamics of a calcium binding epidermal growth factor-like domain pair from the neonatal region of human fibrillin-1. J Biol Chem, 278, 12199-12206. PubMed id: 12511552 DOI: 10.1074/jbc.M208266200
02-May-02     Release date:   29-Apr-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P35555  (FBN1_HUMAN) -  Fibrillin-1
2871 a.a.
86 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     proteinaceous extracellular matrix   1 term 
  Biochemical function     extracellular matrix structural constituent     2 terms  


DOI no: 10.1074/jbc.M208266200 J Biol Chem 278:12199-12206 (2003)
PubMed id: 12511552  
Solution structure and dynamics of a calcium binding epidermal growth factor-like domain pair from the neonatal region of human fibrillin-1.
R.S.Smallridge, P.Whiteman, J.M.Werner, I.D.Campbell, P.A.Handford, A.K.Downing.
Fibrillin-1 is a mosaic protein mainly composed of 43 calcium binding epidermal growth factor-like (cbEGF) domains arranged as multiple, tandem repeats. Mutations within the fibrillin-1 gene cause Marfan syndrome (MFS), a heritable disease of connective tissue. More than 60% of MFS-causing mutations identified are localized to cbEGFs, emphasizing that the native properties of these domains are critical for fibrillin-1 function. The cbEGF12-13 domain pair is within the longest run of cbEGFs, and many mutations that cluster in this region are associated with severe, neonatal MFS. The NMR solution structure of Ca(2+)-loaded cbEGF12-13 exhibits a near-linear, rod-like arrangement of domains. This observation supports the hypothesis that all fibrillin-1 (cb)EGF-cbEGF pairs, characterized by a single interdomain linker residue, possess this rod-like structure. The domain arrangement of cbEGF12-13 is stabilized by additional interdomain packing interactions to those observed for cbEGF32-33, which may help to explain the previously reported higher calcium binding affinity of cbEGF13. Based on this structure, a model of cbEGF11-15 that encompasses all known neonatal MFS missense mutations has highlighted a potential binding region. Backbone dynamics data confirm the extended structure of cbEGF12-13 and lend support to the hypothesis that a correlation exists between backbone flexibility and cbEGF domain calcium affinity. These results provide important insight into the potential consequences of MFS-associated mutations for the assembly and biomechanical properties of connective tissue microfibrils.
  Selected figure(s)  
Figure 1.
Fig. 1. Schematic illustration of the secondary structure and consensus sequence of the cbEGF12-13 domain pair from human fibrillin-1 (a) and the position of cbEGF12-13 mapped onto the domain organization of human fibrillin-1 (b). In a conserved cysteine residues are shown in light gray, and the calcium binding consensus sequence is shaded dark gray. indicates a potential -hydroxylation site. Point mutations in cbEGF12-13 associated with MFS are highlighted. Underlined and plain text mutations are known to cause neonatal and classic MFS, respectively. A double mutation is highlighted by asterisks. The G1127S and V1128I missense mutations, shown in italics, are associated with related disorders. Mutation data were obtained from the Marfan syndrome data base on the World Wide Web (6, 13, 65, 66). In b, the position of the neonatal region (as defined by mutation studies) is highlighted.
Figure 5.
Fig. 5. Model of cbEGF11-15 from human fibrillin-1 highlighting MFS-causing mutations in this region. cbEGF11-15 was modeled based on the coordinates of cbEGF12-13 using Insight II (version 2000; MSI Inc.). Calcium atoms are not shown. Residues causing nMFS, MFS , and related disorders are shown in red, cyan, and yellow, respectively. Two mutations resulting in atypically severe MFS phenotypes are highlighted in magenta. Two potential N-linked glycosylation sites, Asn1067 in cbEGF11 and Asn1149 in cbEGF13, are colored green. Mutations that change side chain calcium ligands are boxed. An asterisk indicates a double mutation that was identified. It is currently unknown whether these were on the same or different alleles. Only non-cysteine mutations were considered here, because cysteine mutations are likely to affect protein folding rather than protein-protein interactions.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 12199-12206) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21175431 I.Robertson, S.Jensen, and P.Handford (2010).
TB domain proteins: evolutionary insights into the multifaceted roles of fibrillins and LTBPs.
  Biochem J, 433, 263-276.  
19533785 B.H.Chung, S.T.Lam, T.M.Tong, S.Y.Li, K.S.Lun, D.H.Chan, S.F.Fok, J.S.Or, D.K.Smith, W.Yang, and Y.L.Lau (2009).
Identification of novel FBN1 and TGFBR2 mutations in 65 probands with Marfan syndrome or Marfan-like phenotypes.
  Am J Med Genet A, 149, 1452-1459.  
19446531 S.A.Jensen, S.Iqbal, E.D.Lowe, C.Redfield, and P.A.Handford (2009).
Structure and interdomain interactions of a hybrid domain: a disulphide-rich module of the fibrillin/LTBP superfamily of matrix proteins.
  Structure, 17, 759-768.
PDB code: 2w86
19473076 Y.Chen, Y.P.Lei, H.X.Zheng, W.Wang, H.B.Cheng, J.Zhang, H.Y.Wang, L.Jin, and H.Li (2009).
A novel mutation (C1425Y) in the FBN2 gene in a father and son with congenital contractural arachnodactyly.
  Genet Test Mol Biomarkers, 13, 295-300.  
18280495 E.Johnson, L.Bruschweiler-Li, S.A.Showalter, G.W.Vuister, F.Zhang, and R.Brüschweiler (2008).
Structure and dynamics of Ca2+-binding domain 1 of the Na+/Ca2+ exchanger in the presence and in the absence of Ca2+.
  J Mol Biol, 377, 945-955.  
18785925 S.Li, W.Yang, A.W.Maniccia, D.Barrow, H.Tjong, H.X.Zhou, and J.J.Yang (2008).
Rational design of a conformation-switchable Ca2+- and Tb3+-binding protein without the use of multiple coupled metal-binding sites.
  FEBS J, 275, 5048-5061.  
16880403 C.Baldock, V.Siegler, D.V.Bax, S.A.Cain, K.T.Mellody, A.Marson, J.L.Haston, R.Berry, M.C.Wang, J.G.Grossmann, M.Roessle, C.M.Kielty, and T.J.Wess (2006).
Nanostructure of fibrillin-1 reveals compact conformation of EGF arrays and mechanism for extensibility.
  Proc Natl Acad Sci U S A, 103, 11922-11927.  
16571647 P.N.Robinson, E.Arteaga-Solis, C.Baldock, G.Collod-Béroud, P.Booms, A.De Paepe, H.C.Dietz, G.Guo, P.A.Handford, D.P.Judge, C.M.Kielty, B.Loeys, D.M.Milewicz, A.Ney, F.Ramirez, D.P.Reinhardt, K.Tiedemann, P.Whiteman, and M.Godfrey (2006).
The molecular genetics of Marfan syndrome and related disorders.
  J Med Genet, 43, 769-787.  
16677079 P.Whiteman, S.Hutchinson, and P.A.Handford (2006).
Fibrillin-1 misfolding and disease.
  Antioxid Redox Signal, 8, 338-346.  
15861007 C.Boileau, G.Jondeau, T.Mizuguchi, and N.Matsumoto (2005).
Molecular genetics of Marfan syndrome.
  Curr Opin Cardiol, 20, 194-200.  
16222666 K.M.Summers, M.Nataatmadja, D.Xu, M.J.West, J.J.McGill, C.Whight, A.Colley, and L.C.Adès (2005).
Histopathology and fibrillin-1 distribution in severe early onset Marfan syndrome.
  Am J Med Genet A, 139, 2-8.  
15103144 R.J.Abbott, V.Knott, P.Roversi, S.Neudeck, P.Lukacik, P.A.Handford, and S.M.Lea (2004).
Crystallization and preliminary X-ray diffraction analysis of three EGF domains of EMR2, a 7TM immune-system molecule.
  Acta Crystallogr D Biol Crystallogr, 60, 936-938.  
15576031 S.Hambleton, N.V.Valeyev, A.Muranyi, V.Knott, J.M.Werner, A.J.McMichael, P.A.Handford, and A.K.Downing (2004).
Structural and functional properties of the human notch-1 ligand binding region.
  Structure, 12, 2173-2183.
PDB code: 1toz
14531790 M.T.Wolf, B.E.Mucha, M.Attanasio, I.Zalewski, S.M.Karle, H.P.Neumann, N.Rahman, B.Bader, C.A.Baldamus, E.Otto, R.Witzgall, A.Fuchshuber, and F.Hildebrandt (2003).
Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains.
  Kidney Int, 64, 1580-1587.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.