An inhibitor domain in c-Fos regulates activation domains containing the HOB1 motif

The c-Fos protein has three activation modules at its C-terminus, two of which contain motifs (HOB1 and HOB2) which are also present in the activation domains of c-Jun. Here we show the existence of two additional activation modules at the N-terminus of c-Fos, one of which contains a second HOB1 motif (HOB1-N). The N-terminus also contains an inhibitor domain (ID1) which silences HOB1 activity. GAL4 fusion experiments showed that ID1 can specifically silence HOB1-containing activation domains from c-Fos or c-Jun when linked in cis, but will not affect other distinct activation domains. The c-Fos related protein, FosB, also contains an inhibitor domain. Mutagenic and deletion analyses identify an inhibitor motif (IM1) conserved between c-Fos and FosB, which is required for inhibitor function. Mutagenesis of IM1 enhances the ability of c-Fos to activate an AP1 bearing promoter. Finally, squelching experiments suggest that c-Fos ID1 binds a limiting protein involved in inhibition. These results demonstrate the existence of a new class of inhibitor domain within transcriptional activators, which acts in a sequence specific manner to inhibit a subset of activation domains.