PITRM1 interaction studies with amyloidogenic nonapeptide mutants of familial Alzheimer's disease

Amyloid β-protein (ABP) is found to be the major cause for the development of neurodegeneration which leads to Alzheimer's. The Aβ nonapeptide segment, QKLVFFAED (amino acids 15-23) is the highly amyloidogenic central region of Aβ. Familial mutation in Aβ increases the aggregation property of the peptide compared to the Native (Wild) amyloid-beta (Aβ) and these mutations fall on the Aβ nonapeptide segment. The catalytic activity of pitrilysin metallopeptidase 1(PITRM1) with familial mutant Aβ (Flemish, Arctic, Dutch, Italian and Iowa) during interaction is examined using molecular dynamic simulation. The molecular dynamics simulation of PITRM1 and the Aβ nonapeptide segment showed similar RMSD with respect to stability. The active site amino acid (AA) H108, hydrophobic pocket AA residues L111, F123, F124, and L127 and the basic pocket AA residues R888 and H896 showed similar interactions with both wild and familial Aβ. The molecular level interaction between amyloid beta and PITRM1 were similar in the wild and familial mutants except for the Arctic mutant. The hydrophobic interaction was commonly observed between the S1 hydrophobic pocket and the LVFF region, the Arctic mutant showed less hydrogen bond formation consistently when compared to other complexes. This molecular information on catalytic activity suggests that modulating inactive PITRM1 or an increase in expression of PITRM1 can help in eliminating different kinds of familial mutant Aβ in neurodegenerative cells.Communicated by Ramaswamy H. Sarma.