Sandbox Reserved 713: Difference between revisions
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Alzheimer's amyloid precursor protein copper-binding domain | <big>'''Alzheimer's amyloid precursor protein copper-binding domain'''</big> | ||
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{{STRUCTURE_2fkl| PDB=2fkl | SCENE= }} | {{STRUCTURE_2fkl| PDB=2fkl | SCENE= }} | ||
[[Image:2fkl pymol representation.png| thumb | 220px | left| PyMol representation of 2fkl]] | |||
=='''Introduction'''== | =='''Introduction'''== | ||
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'''2FKL''' is located in a transmembrane protein called APP for [[Amyloid precursor protein]]. This domain going from residue 124 to 189 is localized in the extracellular part of APP just between the Growth Factor Domain (GFD) and the Acidic domain, in a region called '''Cu-Binding Domain''' which is able to bind Cu and Zinc. | '''2FKL''' is located in a transmembrane protein called APP for [[Amyloid precursor protein]]. This domain going from residue 124 to 189 is localized in the extracellular part of APP just between the Growth Factor Domain (GFD) and the Acidic domain, in a region called '''Cu-Binding Domain''' which is able to bind Cu and Zinc. | ||
This proteins plays a major role into the development of Alzheimer disease<ref> PMID:12399581 </ref>. APP cleavage by BACE and gamma secretase gives ended rise to the Aβ peptide, which forms at the end an aggregation of amyloid plaques <ref> PMID:2881207 </ref> . | This proteins plays a major role into the development of [[Alzheimer]] disease<ref> PMID:12399581 </ref>. APP cleavage by BACE and gamma secretase gives ended rise to the Aβ peptide, which forms at the end an aggregation of amyloid plaques <ref> PMID:2881207 </ref> . | ||
As the interaction between copper ion and APP can modulate the production of Aβ peptide <ref name="Molecular"> PMID:18030462 </ref> and also the progression of Alzheimer disease, structural studies of the Cu-binding Domain of this protein give a lot of information for the development of novel therapeutics. | |||
=='''Structure'''== | =='''Structure'''== | ||
<Structure load='2fkl' size=' | <Structure load='2fkl' size='500' align='left' background='none' caption=' | ||
[[2fkl]]'/> | |||
===Secondary structure=== | |||
2fkl is constituted by two chains called A and B<ref | 2fkl is constituted by two chains called A and B <ref name="MolecularI"/>. Both chains have the same organization. Each chain also contains an <scene name='Sandbox_Reserved_713/Helice_alpha/1'>alpha-helix</scene> going from residue 147 to 159 packed against a triple-strand beta sheet. The strand <scene name='Sandbox_Reserved_719/Beta1/1'>Beta1</scene> going from residue 133 to 139, the <scene name='Sandbox_Reserved_713/Beta_stream2/1'>Beta2</scene> going from residue 162 to 167, and the <scene name='Sandbox_Reserved_713/Beta_stream3/1'>Beta3</scene> going from residue 181 to 188. There is one more Beta sheet, <scene name='Sandbox_Reserved_713/Beta_0/1'>B0</scene>, formed by the residues 127 to 139 of the B chain. | ||
Between the Cysteine 133 and the Cystein 187 we can find a <scene name='Sandbox_Reserved_719/Disulfide_bond/1'>disulfide bound</scene> which links <scene name='Sandbox_Reserved_713/Disulfide_brige_beta1_3/1'>the strand beta 1 and beta 3</scene> and another one | ===Tertiary structure=== | ||
The three dimensional structure of the Cu-Binding Domain was first determined by resonance multidimensional NMR spectroscopy <ref name="MolecularI"> PMID:12611883 </ref>. More recently, the determination of the crystallographic structure permits to define the molecular interaction between the Cu-Binding Domain and copper.<ref name="Molecular" /> | |||
Between the Cysteine 133 and the Cystein 187 we can find a <scene name='Sandbox_Reserved_719/Disulfide_bond/1'>disulfide bound</scene> which links <scene name='Sandbox_Reserved_713/Disulfide_brige_beta1_3/1'>the strand beta 1 and beta 3</scene> and <scene name='Sandbox_Reserved_713/Bislufide_bridge/1'>another one</scene> between cystein 158 and cystein186 which links the alpha helix to the strand Beta 3. Between the cysteine 144 and the cysteine 174 we can describe another <scene name='Sandbox_Reserved_713/Dislfide_brige_2/1'>disulfide bound</scene>. | |||
In order to improve the stabilization of this structure there is a small <scene name='Sandbox_Reserved_713/Hydrophobic_core/1'>hydrophobic core</scene> which contains 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 <scene name='Sandbox_Reserved_713/Negatively_charged/1'>highly negatively charged</scene> (Glu 156, Glu 160, Glu 183 , Asp 167 et Asp 131 ) and <scene name='Sandbox_Reserved_713/Positively_charged/1'>positively</scene> charged(Lys 132, Lys134, Lys161, His 147, His 151 and Lys 155) | The study of the structure also showed on the surface of the Cu-Binding Site different regions <scene name='Sandbox_Reserved_713/Negatively_charged/1'>highly negatively charged</scene> (Glu 156, Glu 160, Glu 183 , Asp 167 et Asp 131 ) and <scene name='Sandbox_Reserved_713/Positively_charged/1'>positively</scene> 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 <scene name='Sandbox_Reserved_719/Tetrahedral_coordination_spher/1'>tetrahedral metal binding site</scene> also called tetrahedral coordination sphere. | '''His147''', '''His151''', '''Tyr168''', '''Met170''' are residues that have been identified as able to bind copper. Those four residues are forming a <scene name='Sandbox_Reserved_719/Tetrahedral_coordination_spher/1'>tetrahedral metal binding site</scene> also called tetrahedral coordination sphere. | ||
=== Quaternary structure === | |||
Finally, quaternary structure is formed by two chain A and B, however, there are a few contacts between those two chains. | |||
The strand B0 allows thanks to hydrogen bounds some of those interactions. | |||
There are also some Van der Waals interaction betweens diffenents aminoacids located on the two chains such as : <br/> | |||
His147 (A) and Phe135 (B) <br/> | |||
Gly175 (A) and Leu171 (B) <br/> | |||
Asp177 (A) and His137 (B) <br/> | |||
=='''Biological role'''== | =='''Biological role'''== | ||
2FKL | 2FKL belongs 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 drives many biological functions of our organism. But in particular situations like overcconcentration it can also become toxic for the cell. <ref name="Molecular" /> | ||
[[Image:CuI coordination.png | thumb | 220px | | [[Image:CuI coordination.png | thumb | 220px | left | Fig.1: Cu(I) binding geometry]] | ||
[[Image:CuII coordination complex.jpg | thumb | 220px | left| | |||
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 (represented 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 <scene name='Sandbox_Reserved_713/2fk1/1'>the formation of the APP-Cu(II)complex</scene> (represented also in standard atomic colouring in Fig 1)(PDB ID : [http://www.rcsb.org/pdb/explore.do?structureId=2fk1 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). | |||
[[Image:CuII coordination complex.jpg | thumb | 220px | left| Fig.2: Cu(I) binding geometry]] | |||
In the <scene name='Sandbox_Reserved_713/2fk2_complex/1'>Cu(I) binding geometry</scene> (represented in grey in Fig.2)(PDB id [http://www.rcsb.org/pdb/explore.do?structureId=2fk2 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 state is not favorable and can lead to the tranfert of the Cu (I) to others proteins.In Fig.2 standard atomic colouring reprensents the Cu(II)binding form. | |||
=='''Medical Implication'''== | |||
[[Image:Schematic representation of APP processing.jpg | thumb | 250px | right | fig 3 : Schematic representation of APP processing]] | |||
An Alzheimer disease is responsible for the most comon form of dementia among old people. Causes of this disease are not clear but genes and environmental factors seem to play a major role. It is characterized by extensive neuronal death, shrinkage of the brain and also the presence of amyloid plaques into the brain <ref> PMID : 17239395 </ref> | |||
These plaques are concentrated with Aβ peptide which results from the anormal cleavage of APP by successive action of the β and γ secretases, illustrated on fig 3.The alteration in copper homostasis is directly related to the progression of Alzheimer disease. The impact of Cu(II) on the aggregation of Aβ peptide is still discussed even if Cu(II) is find in elevated concentration in these plaques. For more information you can follow the link : [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001767/ Alzheimer disease] | |||
The differents domains involved into the Aβ dimerisation aren't yet wery well known, but it seems that E1 and E2 are playing a major role. E1 contains the copper-binding site domain and also the Growth Factor-like Domain, rather than E2 contains the Central APP domain. Those two regions are located in the extracellurlar space. <ref> PMID : 20400860 </ref> | |||
If the CuBD (located in E1 region) does contribute to APP dimerisation without Cu ions, that means that the Cu binding may reduce Aβ production, either by shifting the monomer-dimer equilibrium to favor monomer form, or by re-orienting the dimer form, which disfavours the Aβ production. <ref name="Molecular" /> | |||
=='''Additionnal Resources'''== | =='''Additionnal Resources'''== | ||
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== '''Contributors''' == | == '''Contributors''' == | ||
Milène Walter, Andréa Mc Cann | Milène Walter, Andréa Mc Cann | ||