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2 Subunit I Domain in Regulation of Integrin 
L2 (LFA-1)1
*
Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037; and
Leukocyte Adhesion Laboratory, Imperial Cancer Research Fund, London, United Kingdom
The 
L I (inserted or interactive) domain of
integrin L
2 undergoes conformational
changes upon activation. Recent studies show that the isolated,
activated L I domain is sufficient for strong ligand
binding, suggesting the 2 subunit to be only indirectly
involved. It has been unclear whether the activity of the
L I domain is regulated by the 2 subunit.
In this study, we demonstrate that swapping the disulfide-linked
CPNKEKEC sequence (residues 169–176) in the 2 I domain
with a corresponding 3 sequence, or mutating
Lys174 to Thr, constitutively activates
L2 binding to ICAM-1. These mutants do
not require Mn2+ for ICAM-1 binding and are insensitive to
the inhibitory effect of Ca2+. We have also localized a
component of the mAb 24 epitope (a reporter of 2
integrin activation) in the CPNKEKEC sequence. Glu173 and
Glu175 of the 2 I domain are identified as
critical for mAb 24 binding. Because the epitope is highly expressed
upon 2 integrin activation, it is likely that the
CPNKEKEC sequence is exposed or undergoes conformational changes upon
activation. Deletion of the L I domain did not eliminate
the mAb 24 epitope. This confirms that the L I domain is
not critical for mAb 24 binding, and indicates that mAb 24 detects a
change expressed in part in the 2 subunit I domain.
These results suggest that the CPNKEKEC sequence of the
2 I domain is involved in regulating the
L I domain.
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