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2FK1

Structure of the Alzheimer's Amyloid Precursor Protein (APP) Copper Binding Domain in 'small unit cell' form, Cu(II)-bound

Summary for 2FK1
Entry DOI10.2210/pdb2fk1/pdb
Related1OWT 2FJZ 2FK2 2FK3
DescriptorAmyloid beta A4 protein precursor, COPPER (II) ION (3 entities in total)
Functional Keywordsalpha-beta two-layered sandwich, cu(ii) coordination, metal binding protein
Biological sourceHomo sapiens (human)
Cellular locationMembrane; Single-pass type I membrane protein: P05067
Total number of polymer chains1
Total formula weight6912.47
Authors
Kong, G.K.-W.,Parker, M.W. (deposition date: 2006-01-03, release date: 2007-01-16, Last modification date: 2023-08-30)
Primary citationKong, G.K.,Adams, J.J.,Harris, H.H.,Boas, J.F.,Curtain, C.C.,Galatis, D.,Masters, C.L.,Barnham, K.J.,McKinstry, W.J.,Cappai, R.,Parker, M.W.
Structural Studies of the Alzheimer's Amyloid Precursor Protein Copper-binding Domain Reveal How it Binds Copper Ions
J.Mol.Biol., 367:148-161, 2007
Cited by
PubMed 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.
PubMed: 17239395
DOI: 10.1016/j.jmb.2006.12.041
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.6 Å)
Structure validation

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