Inflammation: TLR and NOD proteins.

Brent Hamaoka

Appointment Period: 2006-2008 / Grant Years: [22,23]

Inflammation is one of the initial responses our bodies elicit to ward off invading pathogens. Nonetheless, this vital response has been linked to tumor progression and proliferation when inappropriately activated. Nucleotide oligomerization domain (NOD) proteins are believed to be proteins that recognize intracellular pathogen associated molecules. This recognition is believed to then signal an inflammatory response. Of the NOD proteins, NOD-2 has been more thoroughly examined, and studies have indicated that NOD-2 is responsive to a bacterial cell wall component, muramyl dipeptide. However, a direct interaction between the two proteins has not been shown. Toll-like receptors (TLRs) are thought to serve as molecular switches that recognize extracellular pathogen-associated molecules and initiate an inflammatory response. TLRs are good candidates for cancer treatment due to their role in signaling inflammation. The manner in which TLR activators (e.g. TLR directed drugs and the pathogen associated molecules) bind to and activate the TLRs remains poorly understood, which makes designing novel activators and inhibitors for the 10 different TLRs very difficult. The research I have been conducting has been geared toward better understanding how TLRs and NOD-2 recognize molecules by analyzing the three-dimensional structure of their interactions using X-ray crystallography, using this knowledge to design novel and/or more effective TLR or NOD-2 activators and inhibitors.

Bzymek KP, Hamaoka BY, Ghosh P. Two translation products of Yersinia yscQassemble to form a complex essential to type III secretion. Biochemistry. 2012Feb 28;51(8):1669-77. Epub 2012 Feb 15. PubMed PMID: 22320351; PubMed CentralPMCID: PMC3289748.