Latest Findings on Phase Separation of Cytomechanical Proteins
Abstract
The cellular response to mechanical stimuli depends largely on the structure of the cell itself and the abundance of intracellular cytomechanical proteins also plays a key role in the response to the stimulation of external mechanical signals. Liquid-liquid phase separation (LLPS) is the process by which proteins or protein-RNA complexes spontaneously separate and form two distinct "phases", ie, a low-concentration phase coexisting with a high-concentration phase. According to published findings, membrane-free organelles form and maintain their structures and regulate their internal biochemical activities through LLPS. LLPS, a novel mechanism for intracellular regulation of the biochemical reactions of biomacromolecules, plays a crucial role in modulating the responses of cytomechanical proteins. LLPS leads to the formation of highly concentrated liquid-phase condensates through multivalent interactions between biomacromolecules, thereby regulating a series of intracellular life activities. It has been reported that a variety of cytomechanical proteins respond to external mechanical signals through LLPS, which in turn affects biological behaviors such as cell growth, proliferation, spreading, migration, and apoptosis. Herein, we introduced the mechanisms of cytomechanics and LLPS. In addition, we presented the latest findings on cytomechanical protein phase separation, covering such issues as the regulation of focal adhesion maturation and mechanical signal transduction by LIM domain-containing protein 1 (LIMD1) phase separation, the regulation of intercellular tight junctions by zonula occludens (ZO) phase separation, and the regulation of cell proliferation and apoptosis by cytomechanical protein phase separation of the Hippo signaling pathway. The proposition of LLPS provides an explanation for the formation mechanism of intracellular membraneless organelles and supplies new approaches to understanding the biological functions of intracellular physiology or pathology. However, the molecular mechanisms by which LLPS drives focal adhesions and cell-edge dynamics are still not fully understood. It is not clear whether LLPS under in vitro conditions can occur under physiological conditions of organisms. There are still difficulties to be overcome in using LLPS to explain the interactions of multiple intracellular molecules. Researchers should pursue answers to these questions in the future.
Keywords: Liquid-liquid phase separation, Cytomechanics, Cytomechanical protein, Review
Full Text:
PDFReferences
BUTCHER D T, ALLISTON T, WEAVER V M. A tense situation: forcing tumour progression. Nat Rev Cancer,2009,9(2): 108–122. doi: 10. 1038/nrc2544.
JANMEY P A, MCCULLOCH C A. Cell mechanics: integrating cell responses to mechanical stimuli. Annu Rev Biomed Eng,2007,9: 1–34. doi: 10.1146/annurev.bioeng.9.060906.151927.
MARTINAC B, NIKOLAEV Y A, SILVANI G, et al. Cell membrane mechanics and mechanosensory transduction. Curr Top Membr,2020, 86: 83–141. doi: 10.1016/bs.ctm.2020.08.002.
HAREENDRANATH S, SATHIAN S P. Dynamic response of red blood cells in health and disease. Soft Matter,2023,19(6): 1219–1230. doi: 10. 1039/d2sm01090a.
CLARK A G, PALUCH E. Mechanics and regulation of cell shape during the cell cycle. Results Probl Cell Differ,2011,53: 31–73. doi: 10.1007/978-3-642-19065-0_3.
CAILLE N, THOUMINE O, TARDY Y, et al. Contribution of the nucleus to the mechanical properties of endothelial cells. J Biomech, 2002,35(2): 177–187. doi: 10.1016/s0021-9290(01)00201-9.
INGBER D E, TENSEGRITY I. Cell structure and hierarchical systems biology. J Cell Sci,2003,116(Pt 7): 1157–1173. doi: 10.1242/jcs.00359. MITCHISON T J, CHARRAS G T, MAHADEVAN L. Implications of a poroelastic cytoplasm for the dynamics of animal cell shape. Semin Cell Dev Biol,2008,19(3): 215–223. doi: 10.1016/j.semcdb.2008.01.008.
CHANGEDE R, SHEETZ M. Integrin and cadherin clusters: a robust way to organize adhesions for cell mechanics. Bioessays,2017,39(1): 1–12. doi: 10.1002/bies.201600123.
MUI K L, CHEN C S, ASSOIAN R K. The mechanical regulation of integrin-cadherin crosstalk organizes cells, signaling and forces. J Cell Sci,2016,129(6): 1093–1100. doi: 10.1242/jcs.183699.
GUHATHAKURTA P, PROCHNIEWICZ E, THOMAS D D. Actin-myosin interaction: structure, function and drug discovery. Int J Mol Sci, 2018,19(9): 2628. doi: 10.3390/ijms19092628.
SQUIRE J. Special Issue: The actin-myosin interaction in muscle: background and overview. Int J Mol Sci,2019,20(22): 5715. doi: 10.3390/ijms20225715.
ROOT D D. The dance of actin and myosin: a structural and spectroscopic perspective. Cell Biochem Biophys,2002,37(2): 111–139. doi: 10.1385/cbb:37:2:111.
BOEYNAEMS S, ALBERTI S, FAWZI N L, et al. Protein phase separation: a new phase in cell biology. Trends Cell Biol,2018,28(6): 420–435. doi: 10.1016/j.tcb.2018.02.004.
BANANI S F, LEE H O, HYMAN A A, et al. Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol,2017,18(5): 285–298. doi: 10.1038/nrm.2017.7.
KATO M, MCKNIGHT S L. A solid-state conceptualization of information transfer from gene to message to protein. Annu Rev Biochem,2018,87: 351–390. doi: 10.1146/annurev-biochem-061516-044700.
ALBERTI S, GLADFELTER A, MITTAG T. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell,2019,176(3): 419–434. doi: 10.1016/j.cell.2018.12.035.
SHIN Y, BRANGWYNNE C P. Liquid phase condensation in cell physiology and disease. Science,2017,357(6357): eaaf4382. doi: 10.1126/science.aaf4382.
FRANZMANN T M, ALBERTI S. Prion-like low-complexity sequences: key regulators of protein solubility and phase behavior. J Biol Chem, 2019,294(18): 7128–7136. doi: 10.1074/jbc.TM118.001190.
RUFF K M, ROBERTS S, CHILKOTI A, et al. Advances in understanding stimulus-responsive phase behavior of intrinsically disordered protein polymers. J Mol Biol,2018,430(23): 4619–4635. doi: 10.1016/j.jmb.2018.06.031.
NOTT T J, PETSALAKI E, FARBER P, et al. Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol Cell,2015,57(5): 936–947. doi: 10.1016/j. molcel.2015.01.013.
TANIUE K, AKIMITSU N. Aberrant phase separation and cancer. FEBS J,2022,289(1): 17–39. doi: 10.1111/febs.15765.
ELBAUM-GARFINKLE S, KIM Y, SZCZEPANIAK K, et al. The disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics. Proc Natl Acad Sci U S A,2015, 112(23): 7189–7194. doi: 10.1073/pnas.1504822112.
SMITH J, CALIDAS D, SCHMIDT H, et al. Spatial patterning of P granules by RNA-induced phase separation of the intrinsically-disordered protein MEG-3. Elife,2016,5: e21337. doi: 10.7554/eLife.21337.
WANG J, CHOI J M, HOLEHOUSE A S, et al. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell,2018,174(3): 688–699.e16. doi: 10.1016/j.cell.2018. 06.006.
HARMON T S, HOLEHOUSE A S, ROSEN M K, et al. Intrinsically disordered linkers determine the interplay between phase separation and gelation in multivalent proteins. Elife,2017,6: e30294. doi: 10.7554/eLife. 30294.
LIN Y, CURRIE S L, ROSEN M K. Intrinsically disordered sequences enable modulation of protein phase separation through distributed tyrosine motifs. J Biol Chem,2017,292(46): 19110–19120. doi: 10.1074/jbc.M117.800466.
PAK C W, KOSNO M, HOLEHOUSE A S, et al. Sequence determinants of intracellular phase separation by complex coacervation of a disordered protein. Mol Cell,2016,63(1): 72–85. doi: 10.1016/j.molcel.2016.05.042.
WANG B, ZHANG L, DAI T, et al. Liquid-liquid phase separation in human health and diseases. Signal Transduct Target Ther,2021,6(1): 290. doi: 10.1038/s41392-021-00678-1.
CHANGEDE R, XU X, MARGADANT F, et al. Nascent integrin adhesions form on all matrix rigidities after integrin activation. Dev Cell, 2015,35(5): 614–621. doi: 10.1016/j.devcel.2015.11.001.
Refbacks
- There are currently no refbacks.