Systematic Profiling Reveals Propensity of Human Ion Channels for Liquid-Liquid Phase Separation.
- 1Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD)), College of Pharmacy, Harbin Medical University, Harbin 150081, China.
- 2State-Province Key Laboratories of Biomedicine-Pharmaceutics of China and Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
Abstract
Liquid-liquid phase separation (LLPS), a fundamental biophysical process driven by multivalent weak interactions, regulates diverse cellular physiological functions. Ion channels are critical transmembrane protein complexes governing electrophysiological signaling, yet their phase separation characteristics remain largely uncharacterized. Here, we systematically assessed the phase-separation propensity of 140 human ion-channel proteins from the PhaSePred database, and 69 human ion channel proteins were predicted to have a high propensity for LLPS (prediction score ≥ 0.5). Based on the self-assembling phase-separating (PS-Self) and partner-dependent phase-separating (PS-Part) scores of the proteins, we classified ion channel proteins with a ratio (PS-Self/PS-Part) > 1 into the PS-Self group and those with a ratio < 1 into the PS-Part group. Ultimately, 37 proteins were predicted to tend toward PS-Self, and 32 to tend toward PS-Part. Moreover, PS-Self candidates exhibited higher hydropathy and pi-pi contact scores, whereas predicted PS-Part candidates showed higher IDR, LCR, and phosphorylation-associated scores. Experimental analyses identified intracellular regions of CaV1.2, CaV1.3, NaV1.5, and KCa2.2 that formed dynamic condensate-like assemblies when expressed in HeLa cells. Our findings elucidate the phase separation classification and core structural domains mediating LLPS in key ion channels and providing a molecular basis for understanding the pathophysiological roles of ion channel phase separation in cardiac and neurological disorders and may inform the development of phase-separation-targeted diagnostic and therapeutic strategies.
Related
- Label-free morphometric profiling reveals early drug responses in 3D tumor spheroids
- Single-cell profiling reveals disruption of cell-cycle homeostasis following JDP2 depletion in colorectal epithelial cells
- Cell-resolved pharmacodynamic profiling reveals tissue- and cell-population-specific activity of antisense oligonucleotide chemical conjugates in vivo
- 106 Multiplex epitranscriptomic profiling reveals RNA modification signatures of immune activation and therapeutic response in cancer immunology
- Organ-Differentiated Metabolomic Profiling Reveals Putative Associations Between Predicted Bioactivity and Database-Annotated Flavor in Medicinal–Edible Talinum paniculatum (Jacq.) Gaertn
BibTeX
@article{li2026systematic,
title = {{Systematic Profiling Reveals Propensity of Human Ion Channels for Liquid-Liquid Phase Separation.}},
author = {Jiamin Li and Yijing Yao and Ran Yu and Siyu Cui and Yun Dong and Yaqing Lu and Ximing Chen and Longkai Yang and Xin Liu and Ning Wang},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198601},
url = {https://europepmc.org/article/MED/42883847},
note = {CC BY},
}
RIS
TY - JOUR
TI - Systematic Profiling Reveals Propensity of Human Ion Channels for Liquid-Liquid Phase Separation.
AU - Jiamin Li
AU - Yijing Yao
AU - Ran Yu
AU - Siyu Cui
AU - Yun Dong
AU - Yaqing Lu
AU - Ximing Chen
AU - Longkai Yang
AU - Xin Liu
AU - Ning Wang
PY - 2026
DA - 2026/09/25
JO - International journal of molecular sciences
DO - 10.3390/ijms27198601
UR - https://europepmc.org/article/MED/42883847
AB - Liquid-liquid phase separation (LLPS), a fundamental biophysical process driven by multivalent weak interactions, regulates diverse cellular physiological functions. Ion channels are critical transmembrane protein complexes governing electrophysiological signaling, yet their phase separation characteristics remain largely uncharacterized. Here, we systematically assessed the phase-separation propensity of 140 human ion-channel proteins from the PhaSePred database, and 69 human ion channel proteins were predicted to have a high propensity for LLPS (prediction score ≥ 0.5). Based on the self-assembling phase-separating (PS-Self) and partner-dependent phase-separating (PS-Part) scores of the proteins, we classified ion channel proteins with a ratio (PS-Self/PS-Part) > 1 into the PS-Self group and those with a ratio < 1 into the PS-Part group. Ultimately, 37 proteins were predicted to tend toward PS-Self, and 32 to tend toward PS-Part. Moreover, PS-Self candidates exhibited higher hydropathy and pi-pi contact scores, whereas predicted PS-Part candidates showed higher IDR, LCR, and phosphorylation-associated scores. Experimental analyses identified intracellular regions of CaV1.2, CaV1.3, NaV1.5, and KCa2.2 that formed dynamic condensate-like assemblies when expressed in HeLa cells. Our findings elucidate the phase separation classification and core structural domains mediating LLPS in key ion channels and providing a molecular basis for understanding the pathophysiological roles of ion channel phase separation in cardiac and neurological disorders and may inform the development of phase-separation-targeted diagnostic and therapeutic strategies.
SN - 1422-0067
ER -