Structural and functional insights into the p160 Rho-associated coiled-coil-containing protein kinase ROCK

Abstract

Rho-associated protein kinases (ROCK1/2) are critical regulators of fundamental cellular processes and represent promising therapeutic targets for various pathologies, particularly cardiovascular disease. While the terminal globular kinase domain and the PH-C1 tandem (PHn-C1-PHc) are well characterized, the sequence-structure-function relationship of the central amphipathic α-helical segment remains poorly understood. Utilizing an integrative biophysical approach—including multi-angle light scattering (MALS), analytical ultracentrifugation (AUC), small-angle X-ray scattering (SAXS), negative-stain electron microscopy (EM), X-ray crystallography, and 3D molecular modeling—we elucidate the structural organization of the central coiled-coil region of ROCK1. Notably, the 2.2 Å resolution crystal structure of the homology region 1 (HR1) of ROCK1 reveals a canonical parallel coiled-coil dimer. This structural arrangement diverges significantly from the antiparallel coiled-coil HR1 module found in other Rho effector kinases. Combined with the structural reconstitution of full-length ROCK1, our data demonstrates that the central segment of ROCK1 forms a highly elongated coiled-coil dimer. Furthermore, EM analysis of the isolated full coiled-coil domain uncovers a dynamic oligomerization state, transitioning between a dimer and a tetramer. Together, these biophysical insights establish a foundation that opens avenues for future investigation into ROCK1 regulation, activation, and downstream signaling mechanisms.

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BibTeX RIS

BibTeX

@article{dubey2026structural,
  title = {{Structural and functional insights into the p160 Rho-associated coiled-coil-containing protein kinase ROCK}},
  author = {Badri Nath Dubey and Soheila Rezaei Adariani and Lothar Gremer and Radovan Dvorsky and Yan Nie and Ehsan Amin and Jens M. Moll and Sicai Zhang and Sander H. J. Smits and Melissa A. Graewert and Dieter Willbold and Georg Groth and Luitgard Nagel and Sabrina Pospich and Mohammad R. Ahmadian},
  journal = {Communications Chemistry},
  year = {2026},
  month = nov,
  doi = {10.1038/s42004-026-02258-2},
  url = {https://www.nature.com/articles/s42004-026-02258-2},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Structural and functional insights into the p160 Rho-associated coiled-coil-containing protein kinase ROCK
AU  - Badri Nath Dubey
AU  - Soheila Rezaei Adariani
AU  - Lothar Gremer
AU  - Radovan Dvorsky
AU  - Yan Nie
AU  - Ehsan Amin
AU  - Jens M. Moll
AU  - Sicai Zhang
AU  - Sander H. J. Smits
AU  - Melissa A. Graewert
AU  - Dieter Willbold
AU  - Georg Groth
AU  - Luitgard Nagel
AU  - Sabrina Pospich
AU  - Mohammad R. Ahmadian
PY  - 2026
DA  - 2026/11/04
JO  - Communications Chemistry
DO  - 10.1038/s42004-026-02258-2
UR  - https://www.nature.com/articles/s42004-026-02258-2
AB  - Rho-associated protein kinases (ROCK1/2) are critical regulators of fundamental cellular processes and represent promising therapeutic targets for various pathologies, particularly cardiovascular disease. While the terminal globular kinase domain and the PH-C1 tandem (PHn-C1-PHc) are well characterized, the sequence-structure-function relationship of the central amphipathic α-helical segment remains poorly understood. Utilizing an integrative biophysical approach—including multi-angle light scattering (MALS), analytical ultracentrifugation (AUC), small-angle X-ray scattering (SAXS), negative-stain electron microscopy (EM), X-ray crystallography, and 3D molecular modeling—we elucidate the structural organization of the central coiled-coil region of ROCK1. Notably, the 2.2 Å resolution crystal structure of the homology region 1 (HR1) of ROCK1 reveals a canonical parallel coiled-coil dimer. This structural arrangement diverges significantly from the antiparallel coiled-coil HR1 module found in other Rho effector kinases. Combined with the structural reconstitution of full-length ROCK1, our data demonstrates that the central segment of ROCK1 forms a highly elongated coiled-coil dimer. Furthermore, EM analysis of the isolated full coiled-coil domain uncovers a dynamic oligomerization state, transitioning between a dimer and a tetramer. Together, these biophysical insights establish a foundation that opens avenues for future investigation into ROCK1 regulation, activation, and downstream signaling mechanisms.
SN  - 2399-3669
ER  -

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