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Selectivity in the use of Gαi/o-proteins is determined by the DRF motif in CXCR6 and is cell-type specific

Tuesday, October 25, 2011 — Poster Session II

Noon – 2:00 p.m.

Natcher Conference Center




  • S Singh
  • J Foley
  • H Zhang
  • D Hurt
  • J Farber


CXCR6 is expressed on multiple cell types and can be a co-receptor for HIV-1. Except for CXCR6, all human chemokine receptors contain the canonical D3.49R3.50Y3.51 sequence, and all but two contain A3.53 at the cytoplasmic terminus of the third transmembrane helix (H3C). The CXCR6 H3C contains the D3.49R3.50F3.51I3.52V3.53 sequence at positions 126-130. We investigated the importance of canonical and non-canonical amino acids in this region by making point mutations–singly and in combination–and for purposes of comparison, in assays in analogous positions in CCR6. Mutants were analyzed in HEK-293T and Jurkat E6-1 cells. We conclude that 1) H3C sequences are matched, with changes having compensatory effects, 2) H3C residues can affect both ligand binding and receptor signaling independently, 3) H3C residues affect selectivity among G-proteins for receptor signaling, and 4) the affects of H3C residues on G-protein use and receptor function are cell-type specific. Results of molecular modeling and simulation suggest molecular mechanisms by which the mutations have their effect. H3C may serve as an on-off switch for GPCRs and may have broader effects on receptor function. GPCR structure may be constrained by a need to use G-proteins promiscuously in various cell types where a given receptor is expressed.

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