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PDBsum entry 3hop

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protein ligands Protein-protein interface(s) links
Structural protein PDB id
3hop
Jmol
Contents
Protein chains
226 a.a. *
Ligands
PO4 ×2
Waters ×139
* Residue conservation analysis
PDB id:
3hop
Name: Structural protein
Title: Structure of the actin-binding domain of human filamin a
Structure: Filamin-a. Chain: a, b. Fragment: actin-binding domain. Synonym: alpha-filamin, filamin-1, endothelial actin- binding protein, actin-binding protein 280, abp-280, non- muscle filamin. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: flna. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.30Å     R-factor:   0.252     R-free:   0.288
Authors: A.R.Clark,G.M.Sawyer,S.P.Robertson,A.J.Sutherland-Smith
Key ref: A.R.Clark et al. (2009). Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders. Hum Mol Genet, 18, 4791-4800. PubMed id: 19773341
Date:
03-Jun-09     Release date:   13-Oct-09    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P21333  (FLNA_HUMAN) -  Filamin-A
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
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Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
2647 a.a.
226 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     actin binding     1 term  

 

 
Hum Mol Genet 18:4791-4800 (2009)
PubMed id: 19773341  
 
 
Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders.
A.R.Clark, G.M.Sawyer, S.P.Robertson, A.J.Sutherland-Smith.
 
  ABSTRACT  
 
Filamin A (FLNA) crosslinks F-actin and binds proteins consistent with roles integrating cell signalling and the cytoskeleton. FLNA missense mutations are associated with the otopalatodigital syndrome (OPD) spectrum of skeletal disorders, clustering in discrete domains. One cluster is found in the second calponin homology domain of the FLNA actin-binding domain (ABD), implicating this region as essential for mediating correct function. Here we show that OPD (FLNA E254K) fibroblast lysates have equivalent concentrations of FLNA compared with controls and that recombinant FLNA E254K ABD has increased in vitro F-actin binding (K(d) 13 microm) compared with wild type (WT; K(d) 48 microm). These observations are consistent with a gain-of-function mechanism for OPD. We have determined the crystal structures of the WT and E254K FLNA ABDs at 2.3 A resolution, revealing that they adopt similar closed conformations. The E254K mutation removes a conserved salt bridge but does not disrupt the ABD structure. The solution structures are also equivalent as determined by circular dichroism spectroscopy, but differential scanning fluorimetry denaturation showed reduced stability (decreased T(m) of 5.6 degrees C) for E254K relative to WT. Ex vivo characterization of E254K OPD patient fibroblasts revealed they have similar motility and adhesion as control cells, implying that many core functions mediated by FLNA are unaffected, consistent with OPD only affecting specific tissues despite FLNA being widely expressed. These data provide the first biochemical evidence for a gain-of-function mechanism for the OPD disorders, and mechanistically distinguishes them from the loss-of-function phenotypes that manifest as disorders of neuronal migration.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21484998 E.Parrini, I.L.Rivas, J.F.Toral, D.Pucatti, S.Giglio, D.Mei, and R.Guerrini (2011).
In-frame deletion in FLNA causing familial periventricular heterotopia with skeletal dysplasia in males.
  Am J Med Genet A, 155, 1140-1146.  
  21328520 P.Cejudo-Martin, and S.A.Courtneidge (2011).
Podosomal proteins as causes of human syndromes: a role in craniofacial development?
  Genesis, 49, 209-221.  
20955932 C.A.Walsh, and E.C.Engle (2010).
Allelic diversity in human developmental neurogenetics: insights into biology and disease.
  Neuron, 68, 245-253.  
  21031081 C.Foley, K.Roberts, N.Tchrakian, T.Morgan, A.Fryer, S.P.Robertson, and N.Tubridy (2010).
Expansion of the Spectrum of FLNA Mutations Associated with Melnick-Needles Syndrome.
  Mol Syndromol, 1, 121-126.  
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.