Model of Alzheimer's disease amyloid-beta peptide based on a RNA binding protein.
Although Alzheimer's Abeta peptide has been shown to form beta-sheet structure, a high-resolution molecular structure is still unavailable to date. A search for a sequence neighbor using Abeta(10-42) as the query in the Protein Data-Bank (PDB) revealed that an RNA binding protein, AF-Sm1 from Archaeoglobus fulgidus (PDB entry: 1i4k chain Z), shared 36% identical residues. Using AF-Sm1 as a template, we built a molecular model of Abeta(10-42) by applying comparative modeling methods. The model of Abeta(10-42) contains an antiparallel beta-sheet formed by residues 16-23 and 32-41. Hydrophobic surface constituted by residues 17-20 (LVFF) separates distinctly charged regions. Residues that interact with RNA in the AF-Sm1 crystal structure were found to be conserved in Abeta. Using a native gel we demonstrate for the first time that RNA can interact with Abeta and selectively retard the formation of fibrils or higher-order oligomers. We hypothesize that in a similar fashion to AF-Sm1, RNA interacts with Abeta in the beta-hairpin (beta-turn-beta) structure and prevents fibril formation.
Mathura
Venkatarajan S
VS
Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA. venkat@rfdn.org
Paris
Daniel
D
Ait-Ghezala
Ghania
G
Quadros
Amita
A
Patel
Nikunj S
NS
Kolippakkam
Deepak N
DN
Volmar
Claude-Henry
CH
Mullan
Michael J
MJ
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000737:chemistry*; D019843:Archaeal Proteins / Q000032:analysis / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D019281:Dimerization; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000032:analysis / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D016601:RNA-Binding Proteins / Q000032:analysis / Q000737:chemistry; D017411:Ribonucleoproteins, Small Nuclear / Q000032:analysis / Q000737:chemistry*; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid
D016229:Amyloid beta-Peptides; D019843:Archaeal Proteins; D046912:Multiprotein Complexes; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear; C426828:Sm1 protein, Archaeoglobus fulgidus