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The three dimensional structure of the Cu-Binding Domain was first determined by resonance multidimensional NMR spectroscopy (article DOI 10.1074/jbc. M300629200 –2003). More recently, the determination of the crystallographic structure permits to define the molecular interaction between the Cu-Binding Domain and copper.(Kong 2007)

2fkl is constituted by two chains called A and B^[4]. Both chains have the same length and the same organization. Each chain also contains an going from residue 147 to 159 packed against a triple-strand beta sheet. The strand going from residue 133 to 139, the going from residue 162 to 167, and the going from residue 181 to 188. There is one more Beta sheet, B0, formed by the residues 127 to 139 of the B chain.

Between the Cysteine 133 and the Cystein 187 we can find a which links and another one BETWEEN CYSTEIN 158 and CYSTEIN 186 which links the alpha helix to the strand Beta 3. Between the cysteine 144 and the cysteine 174 we can describe another .

In order to improve the stabilization of this structure there is a small which contain different residues from each seconday structure. (Leu 136, Trp 150, Val 153, Ala154, Leu 165, Met 170, Val 182 and Val 185)

The study of the structure also showed on the surface of the Cu-Binding Site different regions (Glu 156, Glu 160, Glu 183 , Asp 167 et Asp 131 ) and charged(Lys 132, Lys134, Lys161, His 147, His 151 and Lys 155)

His147, His151, Tyr168, Met170 are residues that have been identified as able to bind copper. Those four residues are forming a also called tetrahedral coordination sphere.

Biological role

2FKL belong to the domain of APP which is able to bind Cu and zinc. Copper is an important metal to health. It acts as an indispensable catalytic and structural cofactor that drive many biological functions of our organism. But in particular situations like overcconcentration it can also become toxic for the cell. ^[5]

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Thanks to its extracellular Cu-Binding Domain (CuBD) constituated by the amino acids describe above, APP can modulate copper transport and storage. The Cu-binding domain of the apo protein (show in grey in the fig 1 ) seems to be able to fixe Cu(II) and to reduce it into Cu(I). More precisely, the Tyr 168, the His 147 and the His 151 participate in Cu(II) binding but not the Methionine 170. In addition, two molecules of water, one axial and one equatorial (noted Ax and Eq on Fig 1) play an important role in the formation of the APP-Cu(II)complex (represented in standard atomic colouring in Fig 1). (PDB ID : 2fk1). It results that the arrangement of the atoms involved in the Cu(II) binding adopts a square pyramidal geometry which can be classified as a Type 2 non-blueCu(II) center. In this type of center Cu(II) is bound by two or three nitrogene ligands and one or two oxygen ligands. Met170 is supposed to act as an electron donor to Cu(II).

In the Cu(I) binding geometry (represented in grey in Fig 2)(PDB id 2fk2), there is no axial water molecules ; the site adopts also a distorted square planar arrangement which is unfavorable for Cu(I) suggesting that this states is not favorable and can lead to the tranfert of the Cu (I) to others proteins.In Fig 2 standart atomic colouring reprensents the Cu(II)binding form.