Biological Pathway Specificity in the Cell—Does Molecular Diversity Matter?

Abstract

Biology arises from the crowded molecular environment of the cell, rendering it a challenge to understand biological pathways based on the reductionist, low‐concentration in vitro conditions generally employed for mechanistic studies. Recent evidence suggests that low‐affinity interactions between cellular biopolymers abound, with still poorly defined effects on the complex interaction networks that lead to the emergent properties and plasticity of life. Mass‐action considerations are used here to underscore that the sheer number of weak interactions expected from the complex mixture of cellular components significantly shapes biological pathway specificity. In particular, on‐pathway—i.e., “functional”—become those interactions thermodynamically and kinetically stable enough to survive the incessant onslaught of the many off‐pathway (“nonfunctional”) interactions. Consequently, to better understand the molecular biology of the cell a further paradigm shift is needed toward mechanistic experimental and computational approaches that probe intracellular diversity and complexity more directly. Also see the video abstract here https://youtu.be/T19X_zYaBzg.

Hyperosmotic phase separation: Condensates beyond inclusions, granules and organelles

“…In both these perturbations, the phase separation outcome depends on the compound effects of each of these factors in reshaping the phase boundaries and altering the saturation concentration ( Figure 1A, 1B). Furthermore, such perturbations typically represent dynamic non-equilibrium situations within a complex matrix of competing cellular interaction partners (56), which adds to the complexity of studying intracellular phase separation (57,58).…”

“…1 , A – B ). Furthermore, such perturbations typically represent dynamic nonequilibrium situations within a complex matrix of competing cellular interaction partners ( 56 ), which adds to the complexity of studying intracellular phase separation ( 57 , 58 ).…”

System-level analysis of flux regulation of yeast show that glycolytic flux is controlled by allosteric regulation and enzyme phosphorylation

“…This pathway speci c regulation pattern has also been found in E. coli under different chemostat cultures 12 . Moreover, this regulatory pattern seemed to play an important role in response to a speci c environment 28 . For yeast growing under aerobic glucose-limited chemostat, repression of genes involved in oxidative metabolism 17 , together with lower translation e ciency of ribosome 18 led to lower mitochondrial protein levels and a better correlation between protein concentration and metabolic ux was observed.…”

Utilizing functional cell‐free extracts to dissect ribonucleoprotein complex biology at single‐molecule resolution

“…Cell extracts have also been the cornerstone of miRNA research, enabling mechanistic interrogation of miRNA biogenesis (Betancur & Tomari, 2012;Förstemann et al, 2007;Miyoshi et al, 2010;O'Brien et al, 2018), miRISC assembly (Azuma-Mukai et al, 2008;Iwasaki et al, 2010;Kawamata et al, 2009;Kawamata & Tomari, 2011;Yoda et al, 2010) and miRISC-mediated gene regulation (Fukao et al, 2014;Mathonnet et al, 2007;Pillai et al, 2005;Wakiyama et al, 2006;Wakiyama et al, 2007;Wakiyama et al, 2018;B. Wang et al, 2006;B. Wang et al, 2007) at the ensemble level.…”