p105, also known as NF-kappaB1, is an atypical IkappaB molecule with a 
multi-domain organization distinct from other prototypical IkappaBs, like 
IkappaBalpha and IkappaBbeta. To understand the mechanism by which p105 binds 
and inhibits NF-kappaB, we have used both p105 and its C-terminal inhibitory 
segment known as IkappaBgamma for our study. We show here that one IkappaBgamma 
molecule binds to NF-kappaB dimers wherein at least one NF-kappaB subunit is 
p50. We suggest that the obligatory p50 subunit in IkappaBgamma.NF-kappaB 
complexes is equivalent to the N-terminal p50 segment in all p105.NF-kappaB 
complexes. The nuclear localization signal (NLS) of the obligatory p50 subunit 
is masked by IkappaBgamma, whereas the NLS of the nonobligatory NF-kappaB 
subunit is exposed. Thus, the global binding mode of all IkappaB.NF-kappaB 
complexes seems to be similar where one obligatory (or specific) NF-kappaB 
subunit makes intimate contact with IkappaB and the nonobligatory (or 
nonspecific) subunit is bound primarily through its ability to dimerize. In the 
case of IkappaBalpha and IkappaBbeta, the specific NF-kappaB subunit in the 
complex is p65. In contrast to IkappaBalpha.NF-kappaB complexes, where the 
exposed NLS of the nonspecific subunit imports the complex to the nucleus, 
p105.NF-kappaB and IkappaBgamma.NF-kappaB complexes are cytoplasmic. We show 
that the death domain of p105 (also of IkappaBgamma) is essential for the 
cytoplasmic sequestration of NF-kappaB by p105 and IkappaBgamma. However, the 
death domain does not mask the exposed NLS of the complex. We also demonstrate 
that the death domain alone is not sufficient for cytoplasmic retention and 
instead functions only in conjunction with other parts in the three-dimensional 
scaffold formed by the association of the ankyrin repeat domain (ARD) and 
NF-kappaB dimer. We speculate that additional cytoplasmic protein(s) may 
sequester the entire p105.NF-kappaB complex by binding through the death domain 
and other segments, including the exposed NLS.