Stolerman Lucas M, Ghosh Pradipta, Rangamani Padmini
Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA, 92093, USA.
Department of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
Bull Math Biol. 2021 Feb 20;83(4):34. doi: 10.1007/s11538-021-00864-w.
GTPases are molecular switches that regulate a wide range of cellular processes, such as organelle biogenesis, position, shape, function, vesicular transport between organelles, and signal transduction. These hydrolase enzymes operate by toggling between an active ("ON") guanosine triphosphate (GTP)-bound state and an inactive ("OFF") guanosine diphosphate (GDP)-bound state; such a toggle is regulated by GEFs (guanine nucleotide exchange factors) and GAPs (GTPase activating proteins). Here we propose a model for a network motif between monomeric (m) and trimeric (t) GTPases assembled exclusively in eukaryotic cells of multicellular organisms. We develop a system of ordinary differential equations in which these two classes of GTPases are interlinked conditional to their ON/OFF states within a motif through coupling and feedback loops. We provide explicit formulae for the steady states of the system and perform classical local stability analysis to systematically investigate the role of the different connections between the GTPase switches. Interestingly, a coupling of the active mGTPase to the GEF of the tGTPase was sufficient to provide two locally stable states: one where both active/inactive forms of the mGTPase can be interpreted as having low concentrations and the other where both m- and tGTPase have high concentrations. Moreover, when a feedback loop from the GEF of the tGTPase to the GAP of the mGTPase was added to the coupled system, two other locally stable states emerged. In both states the tGTPase is inactivated and active tGTPase concentrations are low. Finally, the addition of a second feedback loop, from the active tGTPase to the GAP of the mGTPase, gives rise to a family of steady states that can be parametrized by a range of inactive tGTPase concentrations. Our findings reveal that the coupling of these two different GTPase motifs can dramatically change their steady-state behaviors and shed light on how such coupling may impact signaling mechanisms in eukaryotic cells.
GTP酶是调节多种细胞过程的分子开关，如细胞器生物发生、位置、形状、功能、细胞器之间的囊泡运输以及信号转导。这些水解酶通过在活性（“开启”）的鸟苷三磷酸（GTP）结合状态和非活性（“关闭”）的鸟苷二磷酸（GDP）结合状态之间切换来发挥作用；这种切换由鸟嘌呤核苷酸交换因子（GEF）和GTP酶激活蛋白（GAP）调节。在这里，我们提出了一个仅在多细胞生物的真核细胞中组装的单体（m）和三聚体（t）GTP酶之间网络基序的模型。我们开发了一个常微分方程组，其中这两类GTP酶通过耦合和反馈回路在一个基序内根据它们的开启/关闭状态相互联系。我们给出了系统稳态的明确公式，并进行了经典的局部稳定性分析，以系统地研究GTP酶开关之间不同连接的作用。有趣的是，活性mGTP酶与tGTP酶的GEF耦合足以提供两个局部稳定状态：一个状态下mGTP酶的活性/非活性形式都可解释为低浓度，另一个状态下mGTP酶和tGTP酶都具有高浓度。此外，当从tGTP酶的GEF到mGTP酶的GAP添加一个反馈回路到耦合系统时，出现了另外两个局部稳定状态。在这两个状态下，tGTP酶都失活，活性tGTP酶浓度较低。最后，添加第二个反馈回路，从活性tGTP酶到mGTP酶的GAP，产生了一系列稳态，这些稳态可以由一系列非活性tGTP酶浓度来参数化。我们的研究结果表明，这两种不同GTP酶基序的耦合可以显著改变它们的稳态行为，并揭示这种耦合可能如何影响真核细胞中的信号传导机制。
