Joel Sussman - Scientific Interests and Contributions

Scientific Interests and Contributions

Sussman was a pioneer of macromolecular refinement, developing CORELS and applying it to yeast tRNAphe. He subsequently determined the structures of 'bulge'-containing DNA fragments as models for insertion mutations.

Sussman's current research focuses on nervous system proteins, especially acetylcholinesterase (AChE), whose 3D structure was first determined in his lab. This structure revealed:

• AChE is a prototype of the α/β hydrolase fold;
• π-cation interactions play a key role in binding of acetylcholine (ACh) and ligands to AChE;
• Its ACh-binding site assisted in structure-based design of promising leads for novel anti-Alzheimer's drugs;
• Discovered a highly asymmetric charge distribution conserved in 'cholinesterase-like adhesion molecules' (CLAMs), and showed that their cytoplasmic domains are 'intrinsically unfolded' with implications for neural development and plasticity, and led to an algorithm, for predicting whether a protein sequence will fold;
• A novel anchoring device for AChE involving superhelical assembly of its subunits around a polyproline-II helix;
• The specific chemical and structural damage to proteins produced by synchrotron radiation, e.g. cleavage of a specific disulfide bond even at cryo temperatures.

He has investigated the molecular basis for halophilicity and halotolerance, shedding light on the molecular basis of how proteins function over extreme ranges of salt concentration, with unexpected implications for kidney diseases. Recently, he determined the structures of acid-β-glucosidase, a protein defective in Gaucher disease, paving the way to novel therapeutic approaches, and of paraoxonase, a protein relevant to treatment of atherosclerosis.