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Alzheimer's amyloid precursor protein copper-binding domain

spinqualitylabelsall models PDB ID 2fkl Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
2fkl, resolution 2.50Å ()
Gene:	APP (Homo sapiens)
Related:	1owt, 2fjz, 2fk1, 2fk2, 2fk3
Structural annotation: Resources: InterPro : Ipr008154, Ipr013803, Ipr015849, Ipr011178, Ipr002223, Ipr008155 Pfam : PF02177 UniProt : P05067
Functional annotation: Cellular component: coated pit extracellular region integral to plasma membrane integral to membrane membrane cell surface Biological process: cell adhesion neuromuscular process apoptosis cellular copper ion homeostasis endocytosis Notch signaling pathway Molecular function: endopeptidase inhibitor activity identical protein binding binding protein binding serine-type endopeptidase inhibitor activity zinc ion binding heparin binding metal ion binding iron ion binding copper ion binding
Evolutionary conservation: Toggle Conservation Colors: Rows = identical sequences: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
Resources:	FirstGlance, OCA, RCSB, PDBsum
Coordinates:	save as pdb, mmCIF, xml

Contents 1 Introduction 2 Biological Role 3 Structure 4 Medical Implication 5 Additionnal Resources 6 References 7 Contributors

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.

Biological Role

Structure

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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 ...a compléter...

^[5]

^[6]

Medical Implication

Additionnal Resources

References

1. ↑ Selkoe DJ. Alzheimer's disease is a synaptic failure. Science. 2002 Oct 25;298(5594):789-91. PMID:12399581 doi:10.1126/science.1074069
2. ↑ 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
3. ↑ PMCID: PMC2921068
4. ↑ 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
5. ↑ 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
6. ↑ 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

Cys-133 and Cys-187 links strands β1 and β3