Sandbox Reserved 713
From Proteopedia
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| - | =='''Biological Role'''== | ||
=='''Structure'''== | =='''Structure'''== | ||
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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 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 contain different residues from each seconday structure. (leu 136, trp 150, val 153, ala154, leu 165, met 170, val 182 val 185) | 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 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 contain different residues from each seconday structure. (leu 136, trp 150, val 153, ala154, leu 165, met 170, val 182 val 185) | ||
The study of the structure also showed on the surface of the Bu 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 hys 147 his 151 et lys 155) | The study of the structure also showed on the surface of the Bu 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 hys 147 his 151 et lys 155) | ||
| + | Four residus (His-147, His-151, Tyr-168, Met-170) has also been identified as able to bind copper, may be involverd into the copper reduction. those four residues are forming a <scene name='Sandbox_Reserved_719/Tetrahedral_coordination_spher/1'>tetrahedral metal binding site</scene>. | ||
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| + | =='''biological role'''== | ||
| + | APP is a transmembrane metalloprotein, which belongs to a large family of APLP (amyloid precursor-like protein)., Thanks to its extracellular Cu-binding domain (CuBD) constituated by the amino acids describe above, APP can modulate copper transport. The Cu binding domain of the apo protein seem to be able to fixe Cu(II) and to reduce it in Cu(I). More precisely, the Tyr 168, the His 147 and the His 151 participate in Cu (II) binding but not the methionine. In addition two molecule of water one axial and one equatorial play an important role in the formation of the complex APP-Cu(II) complex (pdb ID : 2FK1). The arrangement of the atoms involved in the Cu (II) binding adopt 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 ands oxygen ligands. Meth170 is supposed to act as an electron donor to Cu(II). | ||
| + | In the Cu(I) binding geometry (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. | ||
<ref> PMID:3290901 </ref> | <ref> PMID:3290901 </ref> | ||
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<scene name='Sandbox_Reserved_719/Tetrahedral_coordination_spher/1'>tetrahedral coordination sphere</scene> <br /> | <scene name='Sandbox_Reserved_719/Tetrahedral_coordination_spher/1'>tetrahedral coordination sphere</scene> <br /> | ||
| - | <scene name='Sandbox_Reserved_719/Disulfide_bond/1'>disulfide bound</scene> Cys-133 and Cys-187 links strands β1 and β3 <br /> | ||
Revision as of 16:46, 3 January 2013
Alzheimer's amyloid precursor protein copper-binding domain
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| 2fkl, resolution 2.50Å () | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Gene: | APP (Homo sapiens) | ||||||||
| Related: | 1owt, 2fjz, 2fk1, 2fk2, 2fk3 | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Contents |
Introduction
2fkl is located in the protein called APP Amyloid precursor protein going from residue 126 to 189. This proteins plays a major role into the developpement of alzheimer desease[1]. APP cleavage by BACE and gamma secretase gives endeed rise to the Aβ peptide, which forms at the end an aggegation of amyloid plaques [2] . As the interaction between copper ion and APP can modulate the production of Aβ pepetide [3] and also the progression of Alzheimer disease, the structure study of the Cu-binding site of this protein can give a lot of informations for the developpement of novel therapeutics.
Structure
|
The three dimensional structure of the Cu Binding Site was determined by resonance multidimensional NMR spectroscopy.
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 the residues 147 to 159 packed against a triple-strand beta sheet. The going from residues 133-139, the going from residues 162-167, and the going from residues 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 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 val 185) The study of the structure also showed on the surface of the Bu binding site different regions (glu 156, glu 160, glu 183 , asp 167 et asp 131 ) and charged(lys 132, lys134, lys161 hys 147 his 151 et lys 155) Four residus (His-147, His-151, Tyr-168, Met-170) has also been identified as able to bind copper, may be involverd into the copper reduction. those four residues are forming a .
biological role
APP is a transmembrane metalloprotein, which belongs to a large family of APLP (amyloid precursor-like protein)., Thanks to its extracellular Cu-binding domain (CuBD) constituated by the amino acids describe above, APP can modulate copper transport. The Cu binding domain of the apo protein seem to be able to fixe Cu(II) and to reduce it in Cu(I). More precisely, the Tyr 168, the His 147 and the His 151 participate in Cu (II) binding but not the methionine. In addition two molecule of water one axial and one equatorial play an important role in the formation of the complex APP-Cu(II) complex (pdb ID : 2FK1). The arrangement of the atoms involved in the Cu (II) binding adopt 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 ands oxygen ligands. Meth170 is supposed to act as an electron donor to Cu(II). In the Cu(I) binding geometry (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.
Medical Implication
Additionnal Resources
References
- ↑ Selkoe DJ. Alzheimer's disease is a synaptic failure. Science. 2002 Oct 25;298(5594):789-91. PMID:12399581 doi:10.1126/science.1074069
- ↑ Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19-25;325(6106):733-6. PMID:2881207 doi:http://dx.doi.org/10.1038/325733a0
- ↑ PMCID: PMC2921068
- ↑ Barnham KJ, McKinstry WJ, Multhaup G, Galatis D, Morton CJ, Curtain CC, Williamson NA, White AR, Hinds MG, Norton RS, Beyreuther K, Masters CL, Parker MW, Cappai R. Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. J Biol Chem. 2003 May 9;278(19):17401-7. Epub 2003 Feb 28. PMID:12611883 doi:10.1074/jbc.M300629200
- ↑ Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon RA, Scolnick EM, Sigal IS. Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4686-90. PMID:3290901
- ↑ Barnham KJ, McKinstry WJ, Multhaup G, Galatis D, Morton CJ, Curtain CC, Williamson NA, White AR, Hinds MG, Norton RS, Beyreuther K, Masters CL, Parker MW, Cappai R. Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. J Biol Chem. 2003 May 9;278(19):17401-7. Epub 2003 Feb 28. PMID:12611883 doi:10.1074/jbc.M300629200
Contributors
Milène Walter, Andréa Mc Cann
