Rule-based modelling of clathrin polymerisation
Creators: name: Sorokin, Anatoly
name: Heil, Katharina
name: J. Douglas Armstrong
name: Sorokina, Oksana
Publisher: name: F1000Research
Year: 2016

description: Clathrin is the major component of clathrin-mediated endocytosis (CME). Due to the particular shape and (auto-) polymerisation capacity, when activated, clathrin forces the cell membrane to adapt a vesicular shape. The process is believed to be initiated by a range of different triggers, which forces further molecules to assemble on the extra- and intracellular side of the membrane so that ~30 proteins directly participate in the regulation of different steps of endocytosis<sup>1</sup>.<br>Within the cell clathrin molecules tend to form trimers (triskelia), consistent of three clathrin molecules. Within the triskelia structure, one clathrin molecule is often referred to as one leg of a clathrin triskelia. Due to its internal trimeric structure, every single clathrin in the triskelia complex can bind to another clathrin, part of another clathrin triskelia. Hence, every triskelion is able to undergo interactions with three further triskelia. This leads to the formation of dimers and trimers up to large polymers. In a biological context, however, loops of hexagonal and pentagonal shapes are among the most observed. A certain combination of these loops induces the formation of closed cage structures. Three well-known closed structures, mini-coat, hexagonal barrel and soccer ball.<br>Understanding of CME is not possible without the proper understanding of its key process, cage formation. A number of models have been developed to describe the formation of clathrin cages<sup>2</sup> or pits and vesicles<sup>3</sup>. Most of the theoretical works study the thermodynamic equilibrium of the cage or the process of the cage formation with clathrin taken in isolation. It was shown recently that cage formation may start from the flat raft buildup, which is getting transferred into the curvature structure later<sup>4</sup>. Creation of the curved surface will require rearrangement of an internal structure of the already formed pit and, likely controlled by third molecules.<br><br>We have created the rule-based model, describing polymerisation of the clathrin and various scenarios of the cage formation, which is able to reproduce budding of the cage from the flat raft. The key importance of our model is that it is able to serve as an assembly point for the large, biologically meaningful mechanistic model.<br>References<br><br><br> 	McMahon HT &amp; Boucrot E. Molecular mechanism and physiological functions of clathrin-mediated endocytosis. <i>Nat Rev Mol Cell Biol</i> 12, 8:517-533 (2011). doi: 10.1038/nrm3151	<br><br><br><br> 	den Otter WK, Renes MR &amp; Briels WJ. Asymmetry as the key to clathrin cage assembly. <i>Biophys J</i> 99, 4:1231-1238 (2010). doi: 10.1016/j.bpj.2010.06.011	<br><br><br><br> 	Banerjee A, Berezhkovskii A &amp; Nossal R. Stochastic model of clathrin-coated pit assembly. <i>Biophys J</i> 102, 12:2725-2730 (2012). doi: 10.1016/j.bpj.2012.05.010	<br><br><br><br> 	Avinoam O, Schorb M, Beese CJ, Briggs JA &amp; Kaksonen M. Endocytic sites mature by continuous bending and remodeling of the clathrin coat. <i>Science</i> 348, 6241:1369-1372 (2015). doi: 10.1126/science.aaa9555	<br><br><br>