Integrated structural modeling and super-resolution imaging resolve GPCR oligomers

TY - CHAP

T1 - Integrated structural modeling and super-resolution imaging resolve GPCR oligomers

AU - Fanelli, Francesca

AU - Hanyaloglu, Aylin C.

AU - Jonas, Kim

PY - 2020/1/1

Y1 - 2020/1/1

N2 - Formation of G protein-coupled receptors (GPCRs) dimers and higher order oligomers represents a key mechanism in pleiotropic signaling, yet how individual protomers function within oligomers remains poorly understood. For the Class A/rhodopsin subfamily of glycoprotein hormone receptors (GpHRs), di/oligomerization has been demonstrated to play a significant role in regulating its signaling activity at a cellular and physiological level and even pathophysiologically. Here we will describe and discuss the developments in our understanding of GPCR oligomerization, in both health and disease, from the study of this unique and complex subfamily of GPCRs with light on the luteinizing hormone receptor (LHR). Focus will be put on the results of an approach relying on the combination of atomistic modeling by protein-protein docking with super-resolution imaging. The latter could resolve single LHR molecules to ~ 8 nm resolution in functional asymmetric dimers and oligomers, using dual-color photoactivatable dyes and localization microscopy (PD-PALM). Structural modeling of functionally asymmetric LHR trimers and tetramers strongly aligned with PD-PALM-imaged spatial arrangements, identifying multiple possible helix interfaces mediating inter-protomer associations. Diverse spatial and structural assemblies mediating GPCR oligomerization may acutely fine-tune the cellular signaling profile.

AB - Formation of G protein-coupled receptors (GPCRs) dimers and higher order oligomers represents a key mechanism in pleiotropic signaling, yet how individual protomers function within oligomers remains poorly understood. For the Class A/rhodopsin subfamily of glycoprotein hormone receptors (GpHRs), di/oligomerization has been demonstrated to play a significant role in regulating its signaling activity at a cellular and physiological level and even pathophysiologically. Here we will describe and discuss the developments in our understanding of GPCR oligomerization, in both health and disease, from the study of this unique and complex subfamily of GPCRs with light on the luteinizing hormone receptor (LHR). Focus will be put on the results of an approach relying on the combination of atomistic modeling by protein-protein docking with super-resolution imaging. The latter could resolve single LHR molecules to ~ 8 nm resolution in functional asymmetric dimers and oligomers, using dual-color photoactivatable dyes and localization microscopy (PD-PALM). Structural modeling of functionally asymmetric LHR trimers and tetramers strongly aligned with PD-PALM-imaged spatial arrangements, identifying multiple possible helix interfaces mediating inter-protomer associations. Diverse spatial and structural assemblies mediating GPCR oligomerization may acutely fine-tune the cellular signaling profile.

KW - Dimer

KW - Glycoprotein hormone receptors

KW - Luteinizing hormone receptor

KW - Molecular modeling

KW - Molecular recognition

KW - Protein-protein docking

KW - Signaling

KW - Super-resolution imaging

UR - http://www.scopus.com/inward/record.url?scp=85076513805&partnerID=8YFLogxK

U2 - 10.1016/bs.pmbts.2019.11.005

DO - 10.1016/bs.pmbts.2019.11.005

M3 - Chapter

AN - SCOPUS:85076513805

SN - 9780128179291

VL - 169

T3 - Progress in Molecular Biology and Translational Science

SP - 151

EP - 179

BT - Progress in Molecular Biology and Translational Science

A2 - Giraldo, Jesús

A2 - Ciruela, Francisco

PB - Elsevier B.V.

ER -