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<p>Memory formation, fertilization, and cardiac function rely on precise Ca<sup>2+</sup> signaling and subsequent Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII) activation. Ca<sup>2+</sup> sensitivity of the four CaMKII paralogs in mammals is linked to the length of the variable linker region that undergoes extensive alternative splicing. In this study, we determine that the position of charged residues within the linker modulates the Ca<sup>2+</sup>/CaM sensitivity. We present an X-ray crystal structure of the full-length CaMKIIδ holoenzyme consisting of domain-swapped dimers within a dodecameric complex, revealing potential contacts for cooperativity and allostery. Based on molecular dynamics (MD) simulations, small-angle X-ray scattering (SAXS) measurements, and live-cell imaging, we propose a model where the domain-swapped conformation positions the charges of the linker region to drive an interaction with the regulatory segment that modulates the degree of autoinhibition. Our findings provide a framework for understanding allosteric regulation of CaMKII by the linker region in Ca<sup>2+</sup>-sensitive cells.</p>

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A domain-swapped CaMKII conformation facilitates linker-mediated allosteric regulation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月26日

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  • Bao V. Nguyen,
  • Can Özden,
  • Kairong Dong,
  • Oguz Can Koc,
  • Ana P. Torres-Ocampo,
  • Noelle Dziedzic,
  • Daniel Flaherty,
  • Jian Huang,
  • Saketh Sankara,
  • Nikki Lyn Abromson,
  • Diana R. Tomchick,
  • Rafael A. Fissore,
  • Jianhan Chen,
  • Scott C. Garman,
  • Margaret M. Stratton

摘要

Memory formation, fertilization, and cardiac function rely on precise Ca2+ signaling and subsequent Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation. Ca2+ sensitivity of the four CaMKII paralogs in mammals is linked to the length of the variable linker region that undergoes extensive alternative splicing. In this study, we determine that the position of charged residues within the linker modulates the Ca2+/CaM sensitivity. We present an X-ray crystal structure of the full-length CaMKIIδ holoenzyme consisting of domain-swapped dimers within a dodecameric complex, revealing potential contacts for cooperativity and allostery. Based on molecular dynamics (MD) simulations, small-angle X-ray scattering (SAXS) measurements, and live-cell imaging, we propose a model where the domain-swapped conformation positions the charges of the linker region to drive an interaction with the regulatory segment that modulates the degree of autoinhibition. Our findings provide a framework for understanding allosteric regulation of CaMKII by the linker region in Ca2+-sensitive cells.