Complex structure of engineered modular domains defining molecular interaction between ICAM-1 and integrin LFA-1.

TitleComplex structure of engineered modular domains defining molecular interaction between ICAM-1 and integrin LFA-1.
Publication TypeJournal Article
Year of Publication2012
AuthorsKang S, Kim CUn, Gu X, Owens RM, van Rijn SJ, Boonyaleepun V, Mao Y, Springer TA, Jin MM
JournalPLoS One
Volume7
Issue8
Paginatione44124
Date Published2012
ISSN1932-6203
KeywordsAllosteric Regulation, Amino Acid Sequence, Amino Acid Substitution, Crystallography, X-Ray, Directed Molecular Evolution, Humans, Hydrogen Bonding, Intercellular Adhesion Molecule-1, Lymphocyte Function-Associated Antigen-1, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Binding, Protein Interaction Domains and Motifs, Protein Structure, Secondary, Structural Homology, Protein
Abstract

Intermolecular contacts between integrin LFA-1 (α(L)β(2)) and ICAM-1 derive solely from the integrin α(L) I domain and the first domain (D1) of ICAM-1. This study presents a crystal structure of the engineered complex of the α(L) I domain and ICAM-1 D1. Previously, we engineered the I domain for high affinity by point mutations that were identified by a directed evolution approach. In order to examine α(L) I domain allostery between the C-terminal α7-helix (allosteric site) and the metal-ion dependent adhesion site (active site), we have chosen a high affinity variant without mutations directly influencing either the position of the α7-helix or the active sites. In our crystal, the α(L) I domain was found to have a high affinity conformation to D1 with its α7-helix displaced downward away from the binding interface, recapitulating a current understanding of the allostery in the I domain and its linkage to neighboring domains of integrins in signaling. To enable soluble D1 of ICAM-1 to fold on its own, we also engineered D1 to be functional by mutations, which were found to be those that would convert hydrogen bond networks in the solvent-excluded core into vdW contacts. The backbone structure of the β-sandwich fold and the epitope for I domain binding of the engineered D1 were essentially identical to those of wild-type D1. Most deviations in engineered D1 were found in the loops at the N-terminal region that interacts with human rhinovirus (HRV). Structural deviation found in engineered D1 was overall in agreement with the function of engineered D1 observed previously, i.e., full capacity binding to α(L) I domain but reduced interaction with HRV.

DOI10.1371/journal.pone.0044124
Alternate JournalPLoS One
PubMed ID22956999
PubMed Central IDPMC3431320
Grant ListP41 GM103485 / GM / NIGMS NIH HHS / United States
R21 AI079532 / AI / NIAID NIH HHS / United States
GM103485 / GM / NIGMS NIH HHS / United States
Related Institute: 
Molecular Imaging Innovations Institute (MI3)

Weill Cornell Medicine
Department of Radiology
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