Consensus motif for integrin transmembrane helix association.
Interactions between transmembrane (TM) helices play an important role in the regulation of diverse biological functions. For example, the TM helices of integrins are believed to interact heteromerically in the resting state; disruption of this interaction results in integrin activation and cellular adhesion. However, it has been difficult to demonstrate the specificity and affinity of the interaction between integrin TM helices and to relate them to the activation process. To examine integrin TM helix associations, we developed a bacterial reporter system and used it to define the sequence motif required for helix-helix interactions in the beta (1) and beta (3) integrin subfamilies. The helices interact in a novel three-dimensional motif, the "reciprocating large-small motif" that is also observed in the crystal structures of unrelated proteins. Modest but specific stabilization of helix associations is realized via packing of complementary small and large groups on neighboring helices. Mutations destabilizing this motif activate native, full-length integrins. Thus, this highly conserved dissociable motif plays a vital and widespread role as an on-off switch that can integrate with other control elements during integrin activation.
Berger
Bryan W
BW
Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Kulp
Daniel W
DW
Span
Lisa M
LM
DeGrado
Jessica L
JL
Billings
Paul C
PC
Senes
Alessandro
A
Bennett
Joel S
JS
DeGrado
William F
WF
D000595:Amino Acid Sequence; D002460:Cell Line; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics; D019281:Dimerization; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics; D006801:Humans; D039001:Integrin alpha Chains / Q000737:chemistry* / Q000235:genetics; D039641:Integrin beta Chains / Q000737:chemistry* / Q000235:genetics; D019169:Jurkat Cells; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D021122:Protein Subunits