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Structural details of a Class B GPCR-arrestin complex revealed by genetically encoded crosslinkers in living cells

Author

Listed:
  • Yasmin Aydin

    (Leipzig University)

  • Thore Böttke

    (Leipzig University)

  • Jordy Homing Lam

    (University of Southern California)

  • Stefan Ernicke

    (Leipzig University)

  • Anna Fortmann

    (Leipzig University)

  • Maik Tretbar

    (Leipzig University)

  • Barbara Zarzycka

    (Vrije Universiteit Amsterdam)

  • Vsevolod V. Gurevich

    (Vanderbilt University)

  • Vsevolod Katritch

    (University of Southern California
    University of Southern California)

  • Irene Coin

    (Leipzig University)

Abstract

Understanding the molecular basis of arrestin-mediated regulation of GPCRs is critical for deciphering signaling mechanisms and designing functional selectivity. However, structural studies of GPCR-arrestin complexes are hampered by their highly dynamic nature. Here, we dissect the interaction of arrestin-2 (arr2) with the secretin-like parathyroid hormone 1 receptor PTH1R using genetically encoded crosslinking amino acids in live cells. We identify 136 intermolecular proximity points that guide the construction of energy-optimized molecular models for the PTH1R-arr2 complex. Our data reveal flexible receptor elements missing in existing structures, including intracellular loop 3 and the proximal C-tail, and suggest a functional role of a hitherto overlooked positively charged region at the arrestin N-edge. Unbiased MD simulations highlight the stability and dynamic nature of the complex. Our integrative approach yields structural insights into protein-protein complexes in a biologically relevant live-cell environment and provides information inaccessible to classical structural methods, while also revealing the dynamics of the system.

Suggested Citation

  • Yasmin Aydin & Thore Böttke & Jordy Homing Lam & Stefan Ernicke & Anna Fortmann & Maik Tretbar & Barbara Zarzycka & Vsevolod V. Gurevich & Vsevolod Katritch & Irene Coin, 2023. "Structural details of a Class B GPCR-arrestin complex revealed by genetically encoded crosslinkers in living cells," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36797-2
    DOI: 10.1038/s41467-023-36797-2
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    References listed on IDEAS

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    1. Dean P. Staus & Hongli Hu & Michael J. Robertson & Alissa L. W. Kleinhenz & Laura M. Wingler & William D. Capel & Naomi R. Latorraca & Robert J. Lefkowitz & Georgios Skiniotis, 2020. "Structure of the M2 muscarinic receptor–β-arrestin complex in a lipid nanodisc," Nature, Nature, vol. 579(7798), pages 297-302, March.
    2. Arun K. Shukla & Aashish Manglik & Andrew C. Kruse & Kunhong Xiao & Rosana I. Reis & Wei-Chou Tseng & Dean P. Staus & Daniel Hilger & Serdar Uysal & Li-Yin Huang & Marcin Paduch & Prachi Tripathi-Shuk, 2013. "Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide," Nature, Nature, vol. 497(7447), pages 137-141, May.
    3. Yanyong Kang & X. Edward Zhou & Xiang Gao & Yuanzheng He & Wei Liu & Andrii Ishchenko & Anton Barty & Thomas A. White & Oleksandr Yefanov & Gye Won Han & Qingping Xu & Parker W. de Waal & Jiyuan Ke & , 2015. "Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser," Nature, Nature, vol. 523(7562), pages 561-567, July.
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