2018/09/28 by Marcin Leda, Leda, Marcin, Andrew J. Holland +3
Biochemistry, Genetics and Molecular Biology · #Microtubule and mitosis dynamics #Photosynthetic Processes and Mechanisms #Protist diversity and phylogeny
paper · pdf · doi:10.48550/arxiv.1809.11000
Symmetry breaking, a central principle of physics, has been hailed as the\ndriver of self-organization in biological systems in general and biogenesis of\ncellular organelles in particular, but the molecular mechanisms of symmetry\nbreaking only begin to become understood. Centrioles, the structural cores of\ncentrosomes and cilia, must duplicate every cell cycle to ensure their faithful\ninheritance through cellular divisions. Work in model organisms identified\nconserved proteins required for centriole duplication and found that altering\ntheir abundance affects centriole number. However, the biophysical principles\nthat ensure that, under physiological conditions, only a single procentriole is\nproduced on each mother centriole remain enigmatic. Here we propose a\nmechanistic biophysical model for the initiation of procentriole formation in\nmammalian cells. The model faithfully recapitulates the experimentally observed\ntransition from PLK4 uniformly distributed around the mother centriole, the\n"ring", to a unique PLK4 focus, the "spot", that triggers the assembly of a new\nprocentriole. This symmetry breaking requires a dual positive feedback based on\nautocatalytic activation of PLK4 and enhanced centriolar anchoring of PLK4-STIL\ncomplexes by phosphorylated STIL. We find that, contrary to previous proposals,\nin situ degradation of active PLK4 is insufficient to break symmetry. Instead,\nthe model predicts that competition between transient PLK4 activity maxima for\nPLK4-STIL complexes explains both the instability of the PLK4 ring and\nformation of the unique PLK4 spot. In the model, strong competition at\nphysiologically normal parameters robustly produces a single procentriole,\nwhile increasing overexpression of PLK4 and STIL weakens the competition and\ncauses progressive addition of procentrioles in agreement with experimental\nobservations.\n