Permissive transmembrane helix heterodimerization is required for the expression of a functional integrin

Ardcharaporn Vararattanavech, Man Li Tang, Hoi Yeung Li, Chi Hang Wong, S. K.Alex Law, Jaume Torres*, Suet Mien Tan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

The current paradigm is that integrin is activated via inside-out signalling when its cytoplasmic tails and TMs (transmembrane helices) are separated by specific cytosolic protein(s). Perturbations of the helical interface between the α- and β-TMs of an integrin, as a result of mutations, affect its function. Previous studies have shown the requirement for specific pairing between integrin subunits by ectodomain-exchange analyses. It remains unknown whether permissive α/β-TM pairing of an integrin is also required for pairing specificity and the expression of a functionally regulated receptor. We performed scanning replacement of integrin β2-TM with a TM of other integrin β-subunits. With the exception of β4 substitution, others presented β2-integrins with modified phenotypes, either in their expression or ligand-binding properties. Subsequently, we adopted αLβ2 for follow-on experiments because its conformation and affinity-state transitions have been well defined as compared with other members of the β2-integrins. Replacement of β2- with β3-TM generated a chimaeric αLβ2 of an intermediate affinity that adhered to ICAM-1 (intercellular adhesion molecule 1) but not to ICAM-3 constitutively. Replacing αL-TM with αIIb-TM, forming a natural αIIb/β3-TM pair, reversed the phenotype of the chimaera to that of wild-type αLβ2. Interestingly, the replacement of αLβ2- with β3-TM showed neither an extended conformation nor the separation of its cytoplasmic tails, which are well-reported hallmarks of an activated αLβ2, as determined by reporter mAb (monoclonal antibody) KIM127 reactivity and FRET (fluorescence resonance energy transfer) measurements respectively. Collectively, our results suggest that TM pairing specificity is required for the expression of a functionally regulated integrin.

Original languageEnglish
Pages (from-to)495-502
Number of pages8
JournalBiochemical Journal
Volume410
Issue number3
DOIs
Publication statusPublished - Mar 15 2008
Externally publishedYes

ASJC Scopus Subject Areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Keywords

  • αLβ2
  • Cytoplasmic tail
  • Heterodimerization
  • Integrin
  • Intercellular adhesion molecule (ICAM)
  • Transmembrane helix

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