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J. Biol. Chem., Vol. 278, Issue 1, 556-566, January 3, 2003
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B
and Prototypical IBs Use a Similar Mechanism
to Bind but a Different Mechanism to Regulate the Subcellular
Localization of NF-B*
From the Department of Chemistry & Biochemistry, University of
California at San Diego, La Jolla, California 92093-0359
p105, also known as NF-
B1, is an atypical
IB molecule with a multi-domain organization distinct from other
prototypical IBs, like IB
and IB
. To understand the
mechanism by which p105 binds and inhibits NF-B, we have used both
p105 and its C-terminal inhibitory segment known as IB
for our
study. We show here that one IB molecule binds to NF-B dimers
wherein at least one NF-B subunit is p50. We suggest
that the obligatory p50 subunit in
IB·NF-B complexes is equivalent to the N-terminal p50
segment in all p105·NF-B complexes. The nuclear localization signal (NLS) of the obligatory p50 subunit is masked by IB, whereas the NLS of the nonobligatory NF-B subunit is exposed. Thus,
the global binding mode of all IB·NF-B complexes seems to be
similar where one obligatory (or specific) NF-B subunit makes
intimate contact with IB and the nonobligatory (or nonspecific) subunit is bound primarily through its ability to dimerize. In the case
of IB and IB, the specific NF-B subunit in the complex is p65. In contrast to IB·NF-B complexes, where the exposed NLS of the nonspecific subunit imports the complex to the nucleus, p105·NF-B and IB·NF-B complexes are cytoplasmic. We
show that the death domain of p105 (also of IB) is essential for
the cytoplasmic sequestration of NF-B by p105 and IB. 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-B dimer. We speculate that
additional cytoplasmic protein(s) may sequester the entire p105·NF-B complex by binding through the death domain and other segments, including the exposed NLS.
To whom correspondence should be addressed: Dept. of Chemistry & Biochemistry, University of California at San Diego, 9500 Gilman Dr.,
La Jolla, CA 92093-0359. Tel.: 858-822-0469; Fax: 858-534-7042;
E-mail: gghosh@ucsd.edu.
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