The CII protein of bacteriophage lambda is the key regulator for the lytic-lysogenic choice of the viral lifecycle. An unstable homotetrameric transcription activator of the three phage promoters p(E), p(I) and p(aQ), lambdaCII is stabilized by lambdaCIII and destabilized by the host protease, Escherichia coli HflB (FtsH). In addition, other E. coli proteins HflK, HflC and HflD also influence lysogeny by acting upon CII. Among these, HflD (22.9kDa), a peripheral membrane protein that is exposed towards the cytoplasm, interacts with CII and decreases the frequency of lysogenization of lambda by stimulating the degradation of CII. In this study, we show that in addition to helping CII degradation, HflD inhibits the DNA binding by CII, thereby inhibiting CII-dependent transcription activation. From biochemical, biophysical and modelling studies we also suggest that HflD-CII interaction takes place through the Cys31-accessible surface area of monomeric HflD, which binds to tetrameric CII as a 1:1 complex.
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