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Mutagenesis and Functional Analysis of Ion Channels Heterologously Expressed in Mammalian Cells
15:28

Mutagenesis and Functional Analysis of Ion Channels Heterologously Expressed in Mammalian Cells

Published on: October 1, 2010

Point mutations define a mIgM transmembrane region motif that determines intersubunit signal transduction in the

C M Pleiman1, N C Chien, J C Cambier

  • 1Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.

Journal of Immunology (Baltimore, Md. : 1950)
|March 15, 1994
PubMed

Ag binding to the membrane Ig (mIg) substructure of the B cell Ag receptor leads to activation of cytoplasmic effector molecules including blk, fyn, lyn, and/or lck tyrosine kinases that are associated with receptor's dimeric Ig-alpha/Ig-beta transducer substructure. The structural basis of the apparent intermolecular transmission of this information within the receptor complex is unknown. Here we report that conservative point mutation of a sequence, S584-K597, at the cytoplasmic end of the predicted transmembrane spanning domain of the mIgM heavy chain (mu) ablates Ag-activated signal transduction, while having no detectable effect on association of mIgM with Ig-alpha/Ig-beta heterodimers. Specifically, mutation of serine584 to alanine, tyrosine587 to phenylalanine, threonine592 to valine, or lysine597 to isoleucine completely abrogated Ag-induced signal transduction leading to protein tyrosine phosphorylation and Ca2+ mobilization. Interestingly, mutants in the more peripheral of these residues, serine584 to alanine and lysine597 to isoleucine, remained responsive to a monoclonal antireceptor Ab (b-7-6) and all mutants remained responsive to polyclonal antireceptor Ab. These data implicate the polar sequence, -Y587STTVT592-, in transfer of information from ligand binding to transducer substructures within this heterooligomeric receptor complex. They further indicate that receptor activation by ligands that bind with high affinity and/or to constant region mIg epitopes is less dependent on the integrity of this motif.

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