Mahiuddin Ahmed
B.S. Duke University, 2000

3rd Year Medical Student

Advisor: Dr. Steven O. Smith

Department: Biochemistry & Cell Biology

Graduate Program: Biochemistry & Structural Biology

Abstract:

Title:  Structural analysis and inhibition of amyloid-ß assemblies

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, the protelytic cleavage product of the ß- and Y-secratase on the transmembrane amyloid precursor protein (APP). Of particular interest is the structural role of the conserved GxxxG motif at the C-teriminus of amyloid-ß. A combination of high-resolution solid-state NMR and atomic force microscopy (AFM) is being used to determine the structures of oligomers and fibrils. Structural insights gained are being used to rationally design peptides with a GxFxGxF framework to disrupt the hydrophobic core of amyloid-ß oligomers and fibrils. Additionally, the mechanism of inhibition of endogenous human myelin basic protein is also being investigated. The development of structure-specific inhibitors may provide new therapeutic strategies towards ameliorating a wide range of amyloid-specific neurodegenerative and systemic pathologies.

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

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

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

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.

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.

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.*

Hoos MD, Ahmed M, Smith SO, and Van Nostrand WE. (2009). Myelin basic protein binds to and inhibits the fibrillar assembly of Abeta42 in vitro.. Biochemistry. 48(22):4720-7.

Liao MC, Ahmed M, Smith SO, and Van Nostrand WE. (2009). Degradation of amyloid beta protein by purified myelin basic protein. Journal of Biological Chemistry. [Epub ahead of print]

Ahmed M., Davis, JA, Sato T., Ahuja, S., Van Nostrand WE. and Smith S.O. (2009). Transition of neurotoxic Amyloid-ß(1-42) oligomers to fibrils. Nature Structure and Molecular Biology. In revision; provisionally accepted.

Ahmed M., and Smith S.O. Gly-to-Met packing facilitates amyloid fibril formation of human prion peptide 118-135. In preparation.