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Rational design of intercellular adhesion molecule-1 (ICAM-1) variants for antagonizing integrin lymphocyte

Gang Song1, Greg A Lazar, Tanja Kortemme

  • 1CBR Institute for Biomedical Research, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.

The Journal of Biological Chemistry
|December 16, 2005
PubMed

Insights

Researchers engineered a mutant form of intercellular adhesion molecule-1 (ICAM-1) with significantly enhanced binding affinity for lymphocyte function-associated antigen-1 (LFA-1). This engineered ICAM-1 offers potential for targeting immune cell interactions in biological studies and therapies.

Area of Science:

  • Immunology
  • Structural Biology
  • Biochemistry

Background:

  • The interaction between lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) is crucial for immune and inflammatory responses.
  • This adhesive interaction is characterized by low intrinsic affinity, limiting its precise study and therapeutic manipulation.

Purpose of the Study:

  • To engineer novel variants of ICAM-1 with substantially increased binding affinity for LFA-1 using rational design.
  • To explore the potential of these enhanced affinity ICAM-1 mutants for biological research and therapeutic applications.

Main Methods:

  • Employed rational design strategies to introduce specific amino acid substitutions into the ICAM-1 structure.
  • Focused on modifying residues around Glu-34 and altering binding interface edges to enhance LFA-1 interaction.
  • Quantified binding affinity using LFA-1 I domains with intermediate and high affinity.

Main Results:

  • Achieved a 19-fold and 22-fold increase in binding affinity for intermediate- and high-affinity LFA-1 I domains, respectively, with the most improved ICAM-1 mutant.
  • Demonstrated similarly enhanced potency in inhibiting LFA-1-dependent ligand binding and cell adhesion.
  • Successfully engineered a high monomeric affinity adhesion molecule through rational design.

Conclusions:

  • Rational design is an effective strategy for creating novel adhesion molecules with high monomeric affinity.
  • The engineered ICAM-1 mutant shows significant promise for advancing the study of LFA-1-ICAM-1 interactions and developing targeted therapeutics.

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