Abstract
The molecular details underlying the time-dependent assembly of protein complexes in cellular networks, such as those that occur during differentiation, are largely unexplored. Focusing on the calcium-induced differentiation of primary human keratinocytes as a model system for a major cellular reorganization process, we look at the expression of genes whose products are involved in manually-annotated protein complexes. Clustering analyses revealed only moderate co-expression of functionally related proteins during differentiation. However, when we looked at protein complexes, we found that the majority (55%) are composed of non-dynamic and dynamic gene products (‘di-chromatic’), 19% are non-dynamic, and 26% only dynamic. Considering three-dimensional protein structures to predict steric interactions, we found that proteins encoded by dynamic genes frequently interact with a common non-dynamic protein in a mutually exclusive fashion. This suggests that during differentiation, complex assemblies may also change through variation in the abundance of proteins that compete for binding to common proteins as found in some cases for paralogous proteins. Considering the example of the TNF-α/NFκB signaling complex, we suggest that the same core complex can guide signals into diverse context-specific outputs by addition of time specific expressed subunits, while keeping other cellular functions constant. Thus, our analysis provides evidence that complex assembly with stable core components and competition could contribute to cell differentiation.
Highlights
A key question in cellular network biology is how protein complexes assemble and disassemble in a time-dependent manner
Based on the above studies, we reasoned that the assembly of complexes where proteins compete for a common stable core could play a role in cell differentiation. To test this hypothesis and to define complex assembly motifs, we focused on the calcium-induced differentiation of primary human keratinocytes (PHK) as a model system for a large cellular reorganization process [16,17]
We propose that the stable core module connects to both a dynamic peripheral module important for cell cycle arrest during differentiation
Summary
A key question in cellular network biology is how protein complexes assemble and disassemble in a time-dependent manner. Recent work in yeast has predicted that complexes change in composition during the cell cycle, and that complexes consist of both constitutive but non-dynamically expressed, and dynamically expressed subunits, leading to the proposal of ‘just-in-time assembly’ of complexes [6]. Consistent with this concept, relating expression data in different human cell types and tissues to protein complexes showed that non-dynamically expressed proteins extensively interact with tissue-specific expressed proteins, suggesting a tight interplay between core and tissue-specific proteins [7]. What is the proportion of complexes that are permanently assembled, changed during different cellular conditions, or contain both non-dynamic and dynamic subunits (‘dichromatic’ complexes)? Are subunits replaced at structurally overlapping or compatible surfaces of proteins? What is the role of evolutionarily-related paralogs?
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