Human CD94 is a subunit of the disulfide-linked, heterodimeric natural killer (NK) cell surface receptor CD94/NKG2. This receptor, a member of the C-type lectin superfamily, participates in regulating NK cell directed lysis through interaction with the major histocompatibility antigen HLA-E. Two forms of CD94 were expressed using a bacterial expression system and refolded in vitro. One form, residues 34-179, designated S34, corresponds to the entire extracellular region of the receptor, including a 23-residue stem region, and the other, residues 51-179, designated E51, corresponds only to the putative carbohydrate recognition domain of the receptor. The refolded full-length S34 protein existed as a noncovalent dimer initially but formed an interchain disulfide bond upon storage for several months. In contrast, the stemless construct, E51, existed largely as a monomeric form. The stem region of S34, residues 34-56, is sensitive to proteolysis and its absence results in dissociation of the dimer. This suggests that the residues in the stem region of CD94 help to stabilize the dimeric conformation,