Alternative Splicing of a Receptor Intracellular Domain Yields Different Ectodomain Conformations, Enabling Isoform-Selective Functional Ligands

SEAN JMAEFF; KURT DEJGAARD; DAVID Y. THOMAS; FOUAD BRAHIMI; BARCELONA PF; JASON C. YOUNG; H. URI SARAGOVI; ALBA GALAN; NICOLAS DE JAY; CLAUDIA L. KLEINMAN

GISCIENCE & REMOTE SENSING

BELLWETHER PUBL LTD

Año: 2020

1548-1603

Events at a receptor ectodomain affect the intracellular domain conformation, activatingsignal transduction (out-to-in conformational effects). We investigated thereverse direction (in-to-out) where the intracellular domain may impact on ectodomainconformation. The primary sequences of naturally occurring TrkC receptor isoforms(TrkC-FL and TrkC.T1) only differ at the intracellular domain. However, owingto their differential association with Protein Disulfide Isomerase the isoforms havedifferent disulfide bonding and conformations at the ectodomain. Conformationswere exploited to develop artificial ligands, mAbs, and small molecules, with isoform-specific binding and biased activation. Consistent, the physiological ligandsNT-3 and PTP-sigma bind both isoforms, but NT-3 activates all signaling pathways,whereas PTP-sigma activates biased signals. Our data support an ??in-to-out?? modelcontrolling receptor ectodomain conformation, a strategy that enables heterogeneityin receptors, ligands, and bioactivity. These concepts may be extended tothe many wild-type or oncogenic receptors with known isoforms.