Inhibitory effect of truncated isoforms on GPCR dimerization predicted by combinatorial computational strategy

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• G protein-coupled receptors (GPCRs) are crucial in biological processes and disease.
• Alternative splicing generates GPCR isoforms with potentially distinct signaling functions.
• Truncated GPCR isoforms may regulate full-length receptor activity, but their interactions are poorly understood.

Purpose of the Study:

• To computationally investigate the interaction patterns between full-length GPCRs and their truncated isoforms.
• To explore the potential regulatory mechanisms of truncated GPCR isoforms on their full-length counterparts.

Main Methods:

• Utilized AlphaFold2 for structure prediction and protein-protein docking tools.
• Generated complex structures of human GPCRs (ADORA1, mGlu2, SMO) with their truncated isoforms.
• Assessed binding affinity using atomistic molecular dynamics simulations.

Main Results:

• All four studied truncated GPCR isoforms exhibited potent binding to their full-length counterparts.
• The binding interfaces of truncated isoforms overlapped with those of homodimers.
• Findings suggest truncated isoforms can potentially inhibit homodimerization of full-length GPCRs.

Conclusions:

• Truncated GPCR isoforms possess significant binding potential to full-length receptors.
• These interactions suggest a widespread regulatory role for GPCR truncated isoforms.
• The study provides insights into the functional significance of GPCR alternative splicing variants.