NF-κB p50 precursor, p105, contains an internal IκB-like inhibitor that preferentially inhibits p50

Abstract

The p50 subunit of NF‐κB is apparently synthesized as a precursor molecule of 105 kDa (p105); subsequent processing releases the amino‐terminal p50 polypeptide with rel homology, DNA binding activity and transcriptional activation potential. The carboxy‐terminal region of p105 contains seven copies of an ankyrin‐related sequence previously found in several genes involved in differentiation and cell cycle control. Two proteins with IκB activity, MAD‐3 and pp40, have been cloned and found to contain five obvious ankyrin repeats that align with those in the carboxy‐terminus of p105. Both proteins target their inhibitory activity to the p65 subunit of NF‐κB and to c‐rel. Here we show that the bacterially expressed and purified carboxy‐terminal region (CTR) of p105 abolishes the binding of p50 homodimers to a κB motif but minimally affects the binding of p65 homodimers and NF‐κB. By contrast, MAD‐3 inhibits the binding of p65 and NF‐κB but not p50. Both the CTR and MAD‐3 interact with their respective targets through physical association both in vitro and in vivo. The CTR can be expressed as an independent entity and thus may play two roles, as a cis inhibitor built into the p105 molecule and as a trans regulator of p50.

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