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

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-ang...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245047/
https://www.ncbi.nlm.nih.gov/pubmed/34193419
http://dx.doi.org/10.1126/sciadv.abh3805
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author 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.
author_facet 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.
author_sort Kassem, Noah
collection PubMed
description 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.
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spelling pubmed-82450472021-07-13 Order and disorder—An integrative structure of the full-length human growth hormone receptor 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. Sci Adv Research Articles 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. American Association for the Advancement of Science 2021-06-30 /pmc/articles/PMC8245047/ /pubmed/34193419 http://dx.doi.org/10.1126/sciadv.abh3805 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
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.
Order and disorder—An integrative structure of the full-length human growth hormone receptor
title Order and disorder—An integrative structure of the full-length human growth hormone receptor
title_full Order and disorder—An integrative structure of the full-length human growth hormone receptor
title_fullStr Order and disorder—An integrative structure of the full-length human growth hormone receptor
title_full_unstemmed Order and disorder—An integrative structure of the full-length human growth hormone receptor
title_short Order and disorder—An integrative structure of the full-length human growth hormone receptor
title_sort order and disorder—an integrative structure of the full-length human growth hormone receptor
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245047/
https://www.ncbi.nlm.nih.gov/pubmed/34193419
http://dx.doi.org/10.1126/sciadv.abh3805
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