Mahiuddin Ahmed

4th Year Graduate Student

Department: Biochemistry & Cell Biology

Graduate Program: Biochemistry & Structural Biology

Advisor: Dr. Steven O. Smith

Abstract:

Title:  Inhibition of amyloid assemblies using designed peptides, small molecules, and naturally occurring proteins

Amyloid lesions found in several neurodegenerative and systemic diseases result from the alternative folding of cellular proteins into toxic assemblies. The goal of developing specific inhibitors that block oligomer or fibril formation is limited by the lack of high-resolution molecular structures of these assemblies. We are investigating the structure and formation of oligomers and fibrils formed by both amyloid-ß and human prion peptides, with particular interest in the structural role of conserved glycines within long hydrophobic stretches.

A combination of high-resolution solid-state NMR and atomic force microscopy (AFM) are being used to determine the structures of Aß oligomers and fibrils. In particular, the high-resolution distance constraints provided by solid-state NMR are being used to determine the packing interactions of the hydrophobic C-terminal tail of the amyloid-ß peptides, focusing on the terminal four glycines: Gly29, Gly33, Gly37 and Gly38. The data will be used to create three-dimensional models of the hydrophobic core of amyloid-ß oligomers and fibrils. In addition, a novel method of ‘single-touch’ AFM that provides higher resolution than conventional contact and tapping modes is being used to investigate the sequence of assembly from low-order oligomers to fibrils, and the association of these assemblies with model membranes.

These methods are also being used to investigate the hydrophobic core of human prion protein. Solid-state NMR is being used to probe oligomers and fibrils formed by peptides containing Gly119, Gly123, Gly127, and Gly 131, which are analogous to the terminal glycines in Aß.

Structural insights gained are then being used to rationally design both peptide and small molecule inhibitors to disrupt amyloid assembly. The development of structure-specific inhibitors may provide new therapeutic strategies towards ameliorating a wide range of amyloid-specific neurodegenerative and systemic pathologies.

Publications:
(MSTP-supported publications indicated with an *)

*Hoos MD, Ahmed M, Smith SO, and Van Nostrand WE. (2007). Inhibition of familial cerebral amyloid angiopathy mutant amyloid beta-protein fibril assembly by myelin basic protein. Journal of Biological Chemistry. 282(13):9952-61.

Niranjanakumari N, Day-Storms JJ, Ahmed M, Hsieh J, Zahler NH, Venters RA, and Fierke CA. (2007). Probing the architecture of the b. subtilis RNase P holoenzyme active site by crosslinking and affinity cleavage. RNA. 13(4):521-35.

*Sato T., Kienlen-Campard P., Ahmed M., Liu W, Li H, Elliott J.I., Aimoto S., Constantinescu S.N., Octave J.N., Smith S.O. (2006). Inhibitors of amyloid toxicity based on beta-sheet Packing of Abeta40 and Abeta42. Biochemistry. 45:5503-16.

*Mastrangelo, I.A., Ahmed M., Sato T., Liu W., Wang C., Hough P. and Smith S.O. (2006). High Resolution Atomic Force Microscopy of soluble Abeta42 oligomers. Journal of Molecular Biology. 21:358:106-19.

Hu C, Ahmed M, Melia TJ, Sollner TH, Mayer T, Rothman JE. (2003). Fusion of cells by flipped SNAREs. Science. 300:1745-9.

Hunt JA, Ahmed M, Fierke CA. (1999). Metal binding specificity in carbonic anhydrase is influenced by conserved hydrophobic core residues. Biochemistry. 38:9054-62.