Both LCCL-domains of human CRISPLD2 have high affinity for lipid A.

The LCCL-domain is a recently defined protein module present in diverse extracellular multidomain proteins. Practically nothing is known about the molecular function of these domains; based on functional features of proteins harboring LCCL-domains it has been suggested that these domains might function as lipopolysaccharide-binding domains. Here we show that the two LCCL-domains of human CRISPLD2 protein, a lipopolysaccharide-binding serum protein involved in defense against endotoxin shock, have higher affinity for the lipid A, the toxic moiety of lipopolysaccharides than for ipopolysaccharide. Our observation that the LCCL-domains of CRISPLD2 are specific for the toxic lipid A moiety of the endotoxin suggests that it may block the interaction between endotoxins and the host endotoxin receptors without interfering with the development of antibacterial immunity against the polysaccharide moiety of LPS. We suggest that the anti-inflammatory function of CRISPLD2 protein may account for its role in various pathological and developmental processes.