Order and disorder-An integrative structure of the full-length human growth hormone receptor

• Published in: Science advances 2021-06, Vol.7 (27)
• Main Authors: Kassem, Noah, Araya-Secchi, Raul, Bugge, Katrine, Barclay, Abigail, Steinocher, Helena, Khondker, Adree, Wang, Yong, Lenard, Aneta J, Bürck, Jochen, Sahin, Cagla, Ulrich, Anne S, Landreh, Michael, Pedersen, Martin Cramer, Rheinstädter, Maikel C, Pedersen, Per Amstrup, Lindorff-Larsen, Kresten, Arleth, Lise, Kragelund, Birthe B
• Format: Article
• Language: English
• Subjects: Biophysics; Humans; Medicin och hälsovetenskap; Membrane Proteins - chemistry; Molecular Dynamics Simulation; Protein Conformation; Scattering, Small Angle; SciAdv r-articles; Structural Biology; X-Ray Diffraction
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abh3805

Because of its small size (70 kilodalton) and large content of structural disorder (>50%), the human growth hormone receptor (hGHR) falls between the cracks of conventional high-resolution structural biology methods. Here, we study the structure of the full-length hGHR in nanodiscs with small-angle x-ray scattering (SAXS) as the foundation. We develop an approach that combines SAXS, x-ray diffraction, and NMR spectroscopy data obtained on individual domains and integrate these through molecular dynamics simulations to interpret SAXS data on the full-length hGHR in nanodiscs. The hGHR domains reorient freely, resulting in a broad structural ensemble, emphasizing the need to take an ensemble view on signaling of relevance to disease states. The structure provides the first experimental model of any full-length cytokine receptor in a lipid membrane and exemplifies how integrating experimental data from several techniques computationally may access structures of membrane proteins with long, disordered regions, a widespread phenomenon in biology.