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Histidine-rich Ca2+-binding protein stimulates the transport cycle of SERCA through a conformation-dependent fuzzy complex

Temitope I. Ayeotan, Line Cecilie Hansen, View ORCID ProfileThomas Boesen, View ORCID ProfileClaus Olesen, Jesper V. Møller, View ORCID ProfilePoul Nissen, View ORCID ProfileMagnus Kjaergaard
doi: https://doi.org/10.1101/2020.09.17.302869
Temitope I. Ayeotan
1Department of Molecular Biology and Genetics, Aarhus University, Denmark
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Line Cecilie Hansen
1Department of Molecular Biology and Genetics, Aarhus University, Denmark
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Thomas Boesen
2Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Denmark
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Claus Olesen
3Department of Biomedicine, Aarhus University, Denmark
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Jesper V. Møller
3Department of Biomedicine, Aarhus University, Denmark
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Poul Nissen
1Department of Molecular Biology and Genetics, Aarhus University, Denmark
4The Danish Research Institute for Translational Neuroscience (DANDRITE), Aarhus University, Denmark
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  • For correspondence: pn@mbg.au.dk magnus@mbg.au.dk
Magnus Kjaergaard
1Department of Molecular Biology and Genetics, Aarhus University, Denmark
4The Danish Research Institute for Translational Neuroscience (DANDRITE), Aarhus University, Denmark
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  • For correspondence: pn@mbg.au.dk magnus@mbg.au.dk
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Abstract

The histidine-rich Ca2+-binding protein (HRC) stimulates the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) to increase Ca2+-uptake into the lumen. HRC also binds the triadin scaffold in a Ca2+-dependent manner, and HRC tunes both the uptake and release of Ca2+ depending on the concentration in the intracellular Ca2+-stores. We investigated how HRC stimulates SERCA pumping using biochemical and biophysical assays, and show that HRC is an intrinsically disordered protein that binds directly to SERCA via electrostatic interactions. The affinity of the interaction depends on the conformation of SERCA, and HRC binds most tightly in the calcium-released E2P state. This state marks the end of the rate-limiting [Ca2]E1P to E2P transition of SERCA, and suggests that HRC stimulates SERCA by preferentially stabilizing the end point of this transition. HRC remains disordered in the bound state and thus binds in a dynamic, fuzzy complex. The binding of HRC to SERCA shows that fuzzy complexes formed by disordered proteins may be conformation-specific, and use this specificity to modulate the functional cycle of complex molecular machines such as a P-type ATPase.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 18, 2020.
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Histidine-rich Ca2+-binding protein stimulates the transport cycle of SERCA through a conformation-dependent fuzzy complex
Temitope I. Ayeotan, Line Cecilie Hansen, Thomas Boesen, Claus Olesen, Jesper V. Møller, Poul Nissen, Magnus Kjaergaard
bioRxiv 2020.09.17.302869; doi: https://doi.org/10.1101/2020.09.17.302869
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Histidine-rich Ca2+-binding protein stimulates the transport cycle of SERCA through a conformation-dependent fuzzy complex
Temitope I. Ayeotan, Line Cecilie Hansen, Thomas Boesen, Claus Olesen, Jesper V. Møller, Poul Nissen, Magnus Kjaergaard
bioRxiv 2020.09.17.302869; doi: https://doi.org/10.1101/2020.09.17.302869

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