Caspase-1 is an inflammatory caspase, which produces mature forms of interleukin-1 (IL-1) and interleukin-18 (IL-18). Caspase-1 can be activated intracellular danger signal sensor, including cryopyrin. When cryopyrin recognizes infectious agents and other danger signals produced in our body, this protein forms a caspase-1-activating complex by recruiting ASC. Then, ASC can interact with and activate capase-1, which in turn processes pro-IL-1 and pro-IL-18 into their mature forms. Mutations of cryopyrin are associated with cryopyrin-associated periodic syndromes (CAPS), which are members of a growing family of autoinflammaoty diseases. In addition, ASC is often lost in breast tumors and other cancers.

We recently characterized the interaction between ASC and its regulatory protein, POP1 (pyrin domain-only protein1) using NMR and biochemical methods (Figure: Model structure of ASC_PYD/POP1 complex). Our results showed that ASC might be in complex with POP1 and release POP1 to initiate the formation of caspase-1-activating complex upon interacting with activated cryopyrin. Currently, we are trying to obtain detailed structural information about these interactions.

Caspase-1 can be activated by CARD-containing intracellular pathogen receptors, such as Nod1 and Nod2, although the molecular mechanisms remain elusive. To understand Nod1-induced inflammatory signaling pathway, we study the interaction mediated by the CARD of Nod1. Recently, we determined a crystal structure of the CARD of Nod1 (Figure: Structure of homodimeric Nod1_CARD). The structure revealed that this CARD could form a domain-swapped dimer. We are currently investigating to identify the structural cause inducing the conformational changes of the CARD. Top

Death receptors, including Fas and TNFR-1, are membrane-bound receptors containing a DD as their intracelluar part. Upon activation, these receptors activate caspase-8 through their interaction with an adaptor protein FADD (Figure: Structure of homodimeric Nod1_CARD). Activating certain death receptors can selectively kill cancer cells via induction of apoptosis while sparing normal cells. As a result, detailed information of death receptor-induced caspase-8 activation mechanism can provide the basis for novel therapeutic strategies for apoptosis-deficient disorders such as cancer and autoimmune diseases.

We found that the trimerization of Fas is important in interacting with FADD in vitro. Based on our observation, we are trying to reconstitute caspase-8-activating complex and characterize the interactions using biochemical and biophysical methods, including X-ray crystallography and NMR. Top