Human adiponectin receptor AdipoR1 assumes closed and open structures

Hiroaki Tanabe,Junken Aoki,Toshimasa Yamauchi,Yoshifumi Fujii,Masato Iwabu,Mikako Shirouzu,Hiroki Kawana,Takashi Kadowaki,Yoshiaki Kawano,Miki Okada-Iwabu,Masaki Yamamoto,Takaho Terada,Yoshihiro Nakamura,Tomomi Kimura-Someya,Kuniyuki Kano,Masakatsu Hato,Shigeyuki Yokoyama

doi:10.1038/s42003-020-01160-4

Abstract

The human adiponectin receptors, AdipoR1 and AdipoR2, are key anti-diabetic molecules. We previously reported the crystal structures of human AdipoR1 and AdipoR2, revealing that their seven transmembrane helices form an internal closed cavity (the closed form). In this study, we determined the crystal structure of the D208A variant AdipoR1, which is fully active with respect to the major downstream signaling. Among the three molecules in the asymmetric unit, two assume the closed form, and the other adopts the open form with large openings in the internal cavity. Between the closed- and open-form structures, helices IV and V are tilted with their intracellular ends shifted by about 4 and 11 Å, respectively. Furthermore, we reanalyzed our previous wild-type AdipoR1 diffraction data, and determined a 44:56 mixture of the closed and open forms, respectively. Thus, we have clarified the closed-open interconversion of AdipoR1, which may be relevant to its functional mechanism(s).

Highlights

The human adiponectin receptors, AdipoR1 and AdipoR2, are key anti-diabetic molecules
AdipoR1 activates the AMP-activated protein kinase (AMPK)[2,3,4] pathways, while AdipoR2 activates the peroxisome proliferator-activated receptor-α (PPAR-α)[5,6] pathways leading to the increased expression of uncoupling protein 2 (UCP2)[7]
The D208A mutant of AdipoR1 [residues 89–375, designated hereafter as AdipoR1(A208)] retained the full ability to activate AMPK, whereas the corresponding D219A mutant of AdipoR2 [residues 100–386, designated as AdipoR2(A219)] lacked the ability to increase the expression of UCP212

Summary

Introduction

The human adiponectin receptors, AdipoR1 and AdipoR2, are key anti-diabetic molecules. There is an extra electron density near the zinc ion in the major cavity of AdipoR2 [Protein Data Bank (PDB) ID 3WXW], which might be the substrate or product of the putative hydrolytic activity of AdipoR2. Vasiliauskaité-Brooks et al.[13] reported structures of AdipoR2 that are quite similar to our previous closed-form structure, and interpreted the extra electron density in the major cavity as the free fatty acid most abundant in insect cells, oleic acid. They suggested that the free fatty acid is the product of the putative ceramidase activity of AdipoR213. AdipoR1 adopts both the closed and open forms, probably in equilibrium, and their interconversion may be related to the signaling mechanism

Methods

Results

Conclusion