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We describe here an intriguing similarity between a conserved domain of ion carriers in the inner mitochondrial membrane and a functional domain of the first zinc finger of nuclear receptors. The inner membrane of mitochondria controls the energetic exchanges between the oxidative machinery and the rest of the cell. These exchanges are carried out by several transporters that span the inner membrane. Four of these transporters have been purified, cloned, and sequenced (Kramer and Palmieri 1989; Klingenberg 1990; Runswick et al. 1990; Ricquier et al. 199 1); they are the ADP/ATP carrier (AAC), the uncoupling protein (UCP) of brown adipocytes, the phosphate-carrier protein (PCP) , and the oxoglutarate carrier (OGC). All these transporters are significantly similar, belong to the same functional family, and probably share a similar organization in the membrane and are therefore homologous. Moreover, this common organization is also reflected in genes of AAC and UCP (Ricquier et al. 199 1) . Among the mitochondrial carriers, both AAC and UCP bind nucleotides. The AAC exchanges ADP and ATP, whereas the proton-translocating activity of the UCP is inhibited when purine dior trinucleotides are bound. The nuclear receptors of steroid hormones modulate expression of genes through binding to specific DNA sequences that are the hormone-responsive elements. Many nuclear receptors have been cloned and sequenced, and they form a superfamily of “ligand responsive transcription factors” that share the same organization (Evans 1988; Green and Chambon 1988; Struhl 1989). Moreover, the identity of amino acids of the knuckle of zinc fingers involved in the specific binding of nuclear receptors to DNA has been studied (Berg 1989; Danielsen et al. 1989; Mader et al. 1989; Umesono and Evans 1989; Schwabe and Rhodes 199 1) . Our attention has been attracted by a similarity between this part of zinc-finger proteins and a domain of AAC and UCP. This observation raises the question whether these two families of proteins share a homologous domain involved in their respective affinities for nucleotides or DNA. As shown in figure 1, mitochondrial carriers and nuclear receptors share a short amino acid sequence: seven residues of AAC (EGPKAFFK), of eight in the estradiol receptor (EGCKAFFK). We examined an amino acid sequence library containing 7.4 X lo6 residues (NBRF-PIR) and could calculate that the probability of having the proposed similarity simply by chance was 0.048 for the whole library. We conclude that the reported similarity is not fortuitous. The similarity concerns a short domain that is not only common to two different protein families but is also highly conserved in each of the two families. We observed the greatest similarity between nuclear receptors and AAC and UCP, which are mitochondrial carriers that bind nucleotides. Moreover, the similarity is more pronounced between members of the two different families than between members of one family (fig. 2); in particular, the similarity between fungus AAC and mammal AAC can be lower than that between bovine AAC and human estrogen receptor. In this case, when the nine amino acids sequence are

A conserved domain in mitochondrial transporters is homologous to a zinc-finger knuckle of nuclear hormone receptors.