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PDBsum entry 2fkl

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protein Protein-protein interface(s) links
Metal binding protein PDB id
2fkl
Jmol
Contents
Protein chains
64 a.a. *
Waters ×19
* Residue conservation analysis
PDB id:
2fkl
Name: Metal binding protein
Title: Structure of the alzheimer's amyloid precursor protein (app) copper binding domain (residues 126- 189 of app)
Structure: Amyloid beta a4 protein precursor. Chain: a, b. Fragment: residues 124 to 189. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: app. Expressed in: pichia pastoris. Expression_system_taxid: 4922.
Resolution:
2.50Å     R-factor:   0.222     R-free:   0.263
Authors: G.K.-W.Kong,M.W.Parker
Key ref:
G.K.Kong et al. (2007). Structural studies of the Alzheimer's amyloid precursor protein copper-binding domain reveal how it binds copper ions. J Mol Biol, 367, 148-161. PubMed id: 17239395 DOI: 10.1016/j.jmb.2006.12.041
Date:
04-Jan-06     Release date:   16-Jan-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P05067  (A4_HUMAN) -  Amyloid beta A4 protein
Seq:
Struc:
 
Seq:
Struc:
770 a.a.
64 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     nervous system development   1 term 
  Biochemical function     heparin binding     2 terms  

 

 
DOI no: 10.1016/j.jmb.2006.12.041 J Mol Biol 367:148-161 (2007)
PubMed id: 17239395  
 
 
Structural studies of the Alzheimer's amyloid precursor protein copper-binding domain reveal how it binds copper ions.
G.K.Kong, J.J.Adams, H.H.Harris, J.F.Boas, C.C.Curtain, D.Galatis, C.L.Masters, K.J.Barnham, W.J.McKinstry, R.Cappai, M.W.Parker.
 
  ABSTRACT  
 
Alzheimer's disease (AD) is the major cause of dementia. Amyloid beta peptide (Abeta), generated by proteolytic cleavage of the amyloid precursor protein (APP), is central to AD pathogenesis. APP can function as a metalloprotein and modulate copper (Cu) transport, presumably via its extracellular Cu-binding domain (CuBD). Cu binding to the CuBD reduces Abeta levels, suggesting that a Cu mimetic may have therapeutic potential. We describe here the atomic structures of apo CuBD from three crystal forms and found they have identical Cu-binding sites despite the different crystal lattices. The structure of Cu(2+)-bound CuBD reveals that the metal ligands are His147, His151, Tyr168 and two water molecules, which are arranged in a square pyramidal geometry. The site resembles a Type 2 non-blue Cu center and is supported by electron paramagnetic resonance and extended X-ray absorption fine structure studies. A previous study suggested that Met170 might be a ligand but we suggest that this residue plays a critical role as an electron donor in CuBDs ability to reduce Cu ions. The structure of Cu(+)-bound CuBD is almost identical to the Cu(2+)-bound structure except for the loss of one of the water ligands. The geometry of the site is unfavorable for Cu(+), thus providing a mechanism by which CuBD could readily transfer Cu ions to other proteins.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. The structure of CuBD[133-189] in Type A crystal form. This ribbon diagram of apo CuBD[133-189] is shown in stereo view and prepared using BOBSCRIPT.^63 Key residues surrounding the Cu-binding pocket are shown in ball-and-stick.
Figure 4.
Figure 4. The coordination geometry of Cu^2+ and Cu^+ in CuBD and comparison against the apo Type A structure. (a) The Cu^2+ binding geometry in CuBD[133-189]. The ligands are labeled (eq and ax denote the equatorial and axial water molecules). (b) A comparison of the Cu-binding site in the presence (atomic coloring) and absence (grey, apo form) of the Cu^2+. (c) The Cu^+ binding geometry in CuBD[133-189]. (d) A comparison of the Cu-binding site in the presence (atomic coloring) and absence (grey, apo form) of the Cu^+. All panels are in stereo view. The orange sphere represents the Cu^2+ in (a) and (b) or Cu^+ in (c) and (d). The red spheres are water molecules. The 2F[obs]–F[calc] electron density is shown in (a) and (c) in blue mesh and contoured at 1σ level. All Figures were prepared using the program PyMol (DeLano Scientific LLC, San Carlos, CA).
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 367, 148-161) copyright 2007.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19759550 M.G.Botelho, X.Wang, D.J.Arndt-Jovin, D.Becker, and T.M.Jovin (2010).
Induction of terminal differentiation in melanoma cells on downregulation of beta-amyloid precursor protein.
  J Invest Dermatol, 130, 1400-1410.  
20212142 S.O.Dahms, S.Hoefgen, D.Roeser, B.Schlott, K.H.Gührs, and M.E.Than (2010).
Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein.
  Proc Natl Acad Sci U S A, 107, 5381-5386.
PDB code: 3ktm
19452053 D.R.Brown (2009).
Brain proteins that mind metals: a neurodegenerative perspective.
  Dalton Trans, (), 4069-4076.  
18926873 W.H.Suh, K.S.Suslick, G.D.Stucky, and Y.H.Suh (2009).
Nanotechnology, nanotoxicology, and neuroscience.
  Prog Neurobiol, 87, 133-170.  
18030461 C.Aisenbrey, T.Borowik, R.Byström, M.Bokvist, F.Lindström, H.Misiak, M.A.Sani, and G.Gröbner (2008).
How is protein aggregation in amyloidogenic diseases modulated by biological membranes?
  Eur Biophys J, 37, 247-255.  
18030462 G.K.Kong, L.A.Miles, G.A.Crespi, C.J.Morton, H.L.Ng, K.J.Barnham, W.J.McKinstry, R.Cappai, and M.W.Parker (2008).
Copper binding to the Alzheimer's disease amyloid precursor protein.
  Eur Biophys J, 37, 269-279.  
18256819 J.F.Boas, S.C.Drew, and C.C.Curtain (2008).
Applications of electron paramagnetic resonance to studies of neurological disease.
  Eur Biophys J, 37, 281-294.  
18342639 K.J.Barnham, and A.I.Bush (2008).
Metals in Alzheimer's and Parkinson's diseases.
  Curr Opin Chem Biol, 12, 222-228.  
18511537 M.A.Brooks, L.Meslet-Cladiére, M.Graille, J.Kuhn, K.Blondeau, H.Myllykallio, and H.van Tilbeurgh (2008).
The structure of an archaeal homodimeric ligase which has RNA circularization activity.
  Protein Sci, 17, 1336-1345.
PDB code: 2vug
18634877 R.W.Strange, and M.C.Feiters (2008).
Biological X-ray absorption spectroscopy (BioXAS): a valuable tool for the study of trace elements in the life sciences.
  Curr Opin Struct Biol, 18, 609-616.  
18000558 D.Huster, and S.Lutsenko (2007).
Wilson disease: not just a copper disorder. Analysis of a Wilson disease model demonstrates the link between copper and lipid metabolism.
  Mol Biosyst, 3, 816-824.  
  17909280 G.K.Kong, J.J.Adams, R.Cappai, and M.W.Parker (2007).
Structure of Alzheimer's disease amyloid precursor protein copper-binding domain at atomic resolution.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 819-824.
PDB code: 2fma
17428603 M.Gralle, and S.T.Ferreira (2007).
Structure and functions of the human amyloid precursor protein: the whole is more than the sum of its parts.
  Prog Neurobiol, 82, 11-32.  
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.