PDBsum entry 2fk3

Metal binding protein

PDB id: 2fk3

Contents

Protein chains

(+ 2 more) 59 a.a. *

Metals

_CU ×19

Waters ×189

* Residue conservation analysis

PDB id:

2fk3

Name:

Metal binding protein

Title:

Structure of the alzheimer's amyloid precursor protein (app) copper binding domain in 'large unit cell' form

Structure:

Amyloid beta a4 protein precursor. Chain: a, b, c, d, e, f, g, h. Fragment: residues 133 to 189. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: app. Expressed in: pichia pastoris. Expression_system_taxid: 4922.

Resolution:

2.40Å R-factor: 0.208 R-free: 0.248

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

Protein chains

P05067  (A4_HUMAN) -  Amyloid-beta precursor protein from Homo sapiens

Seq: 770 a.a.

Struc: 59 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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.