Cellular quality control (QC) processes operate within all cells and subcellular compartments to ensure that only correctly folded and assembled proteins and protein complexes are deployed. QC machinery includes molecular chaperones, which facilitate folding of nascent chains, and proteolytic machinery which recognizes and destroys misfolded protein or unassembled (orphan) subunits.

Our research is concerned with elucidating the basic molecular mechanisms that underly the recognition and destruction of misfolded proteins in eukaryotic cells and the role of the QC apparatus in human disease.

What are protein aggregates and inclusion bodies?

In cells, aggregated proteins are usually found in inclusion bodies, structures that contain extremely high concentrations of aggregated protein. Inclusion bodies form in cells or organelles when they are forced to express heterologous or mutant proteins. Inclusion bodies can also form upon overexpression of some endogenous proteins, suggesting that the machinery for folding and/or processing can be saturated.

Aggresomes. We have found that protein aggregates in mammalian cells accumulate at a single, juxtanuclear site which we have dubbed the aggresome. Aggresomes form by retrograde transport of aggregated material along microtubule tracks. This movement requires cytoplasmic dynein and dynactin. We are interested in understanding the molecular basis for this transport process. How are aggregated proteins recognized by the dynein/dynactin complex ? What is the functional utility of this transport ?

Aggregation.'Conventional wisdom' is that protein aggregates are non-specific junk piles of misfolded, jumbled proteins, sort of like molecular dustballs, or scrambled eggs. Our data suggest that protein aggregates are alternative conformational states of proteins and that their formation is no less specific than formation of the native state. We are using fluorescence resonance energy transfer (FRET), electron microscopy, and biochemical techniques to study the formation of protein aggregates in vivo.

Inclusion bodies vs. aggregates.Often the terms 'inclusion body' and 'aggregate' are used interchangeably. While this view may be correct in some cases, it can be misleading because inclusion bodies are defined morphologically (by microscopy) and aggregates are protein conformational states and as such should be defined biochemically.