The Ubiquitin Proteasome System

The Mechanism of Lysine Selection

The proper clearance of misfolded proteins is essential for neuronal health.  CHIP is a critical ubiquitin ligase that promotes the degradation of aggregation-prone proteins.  The molecular mechanisms that regulate CHIP and most other ubiquitin ligases are unknown, and this represents a major obstacle in developing drugs that target these pathways.  To address this knowledge gap, we are focusing on understanding the molecular mechanisms by which the UbcH5/CHIP ubiquitination machinery selects substrate lysine residues.  Answering this fundamental question will provide insight into rational drug design targeting the UbcH5/CHIP ubiquitination machinery and its substrates

 

spinocerebellar ataxia ressecive type 16 (SCar16)

Mutations in the ubiquitin ligase CHIp cause scar16.  our lab is currently interested in understanding how these mutations alter chip function.  insight into scar16 mutations may also provide novel insight into how chip functions in preventing age-related neurodegeneartive diseases.

 

N-terminal Ubiquitination

ubiquitination of the n-terminus of proteins has been long known to occur.  we identified the ubiquitin conjugating enzyme ube2w as the first n-terminus modifying enzyme.  we have developed a ube2w knockout mouse to begin and understand the physiological function of ube2w.