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. 2008;9(7):R107.
doi: 10.1186/gb-2008-9-7-r107. Epub 2008 Jul 7.

Protein structure protection commits gene expression patterns

Jianping Chen  1 , Han Liang, Ariel Fernández
Affiliations

Protein structure protection commits gene expression patterns

Jianping Chen et al. Genome Biol. 2008.

Abstract

Background: Gene co-expressions often determine module-defining spatial and temporal concurrences of proteins. Yet, little effort has been devoted to tracing coordinating signals for expression correlations to the three-dimensional structures of gene products.

Results: We performed a global structure-based analysis of the yeast and human proteomes and contrasted this information against their respective transcriptome organizations obtained from comprehensive microarray data. We show that protein vulnerability quantifies dosage sensitivity for metabolic adaptation phases and tissue-specific patterns of mRNA expression, determining the extent of co-expression similarity of binding partners. The role of protein intrinsic disorder in transcriptome organization is also delineated by interrelating vulnerability, disorder propensity and co-expression patterns. Extremely vulnerable human proteins are shown to be subject to severe post-transcriptional regulation of their expression through significant micro-RNA targeting, making mRNA levels poor surrogates for protein-expression levels. By contrast, in yeast the expression of extremely under-wrapped proteins is likely regulated through protein aggregation. Thus, the 85 most vulnerable proteins in yeast include the five confirmed prions, while in human, the genes encoding extremely vulnerable proteins are predicted to be targeted by microRNAs. Hence, in both vastly different organisms protein vulnerability emerges as a structure-encoded signal for post-transcriptional regulation.

Conclusion: Vulnerability of protein structure and the concurrent need to maintain structural integrity are shown to quantify dosage sensitivity, compelling gene expression patterns across tissue types and temporal adaptation phases in a quantifiable manner. Extremely vulnerable proteins impose additional constraints on gene expression: They are subject to high levels of regulation at the post-transcriptional level.

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Figures

Figure 1
Figure 1
Hydrogen-bond pattern and structural vulnerabilities (SEBHs) of the yeast SH3 domain and the human prion protein PrPC. (a) Hydrogen-bond pattern and structural vulnerabilities (SEBHs) of the yeast SH3 domain from a S. cerevisiae 40.4 kDa protein (PDB.1SSH) [17]. The ribbon display is included as a visual aid. The protein backbone is shown as virtual bonds (blue) joining consecutive α-carbons in the peptide chain. Light-grey segments represent well protected backbone hydrogen bonds, and green segments represent SEBHs. The extent of solvent-exposure extent of a hydrogen bond was determined from atomic coordinates by calculating the number of nonpolar groups within its microenvironment (Materials and methods). SEBHs are those backbone hydrogen bonds protected by an insufficient number of nonpolar groups as statistically defined in Materials and methods. The level of structure vulnerability ν, defined as the ratio of SEBHs to the overall number of backbone hydrogen bonds, is 19.0% (ν = 4/21). (b) SEBH-pattern for the cellular structure of the human prion protein PrPC (PDB.1QM0) [18]. Its vulnerability parameter is ν = 63.0%, making it the most vulnerable soluble folder of all structures of unbound proteins reported in the PDB.
Figure 2
Figure 2
Ribbon representation and vulnerability (SEBH) pattern of subunit 1 from the cytochrome b-c1 complex. (a) Ribbon representation and (b) vulnerability (SEBH) pattern of subunit 1 from the cytochrome b-c1 complex (PDB.1KB9) [19]. In b, red segments represent virtual protein backbone bonds, light-grey segments represent well protected backbone hydrogen bonds, and those green segments represent SEBHs. In the cytochrome complex, this protein adopts a highly vulnerable (ν = 57.3%) conformation.
Figure 3
Figure 3
Mutual protection of SEBHs in the two subunits of mitochondrial respiratory chain complex III. (a) Ribbon representation of mitochondrial respiratory chain complex III (PDB.1KB9). The high structure vulnerability of subunit 1 (red; compare Figure 2) renders it highly needy for interaction with other subunits of the complex to maintain its structural integrity. (b) SEBH pattern for subunit 1 (red) and subunit 2 (blue). The interacting pair is characterized by a very high expression correlation η = 3.61. The yellow square highlights the part of the interface shown in detail in (c). (c) Illustration of mutual protections of SEBHs in the two subunits along part of their interface. One side-chain bond (between α and β carbons) is displayed. The thin blue lines, which connect β-carbons in one protein with centers of hydrogen bonds in the other protein, represent mutual protections of hydrogen bonds across the protein-association interface. Thus, a thin line is shown whenever the side chain of one protein is contributing with nonpolar groups to the microenvironment of a preformed hydrogen bond in its binding partner.
Figure 4
Figure 4
Correlation between maximum structure vulnerability ν and co-expression similarity η for yeast protein interactions. (a) Correlation between maximum structure vulnerability ν and co-expression similarity η for interactions within specific yeast complexes. The ν-parameter of an interaction is defined as the maximum vulnerability between the two interacting partners, and the η-parameter is the ratio of their expression correlation to the (non-zero) expected correlation over all interacting pairs in the proteome. (b) (η-ν) correlation for all Pfam-filtered yeast protein interactions. Red points represent interactions involving extremely vulnerable proteins, including confirmed yeast prions (Additional data file 5). (c) (η-ν) correlation of Pfam-filtered yeast protein interactions involving only PDB-reported proteins. The red data point represents an interaction involving an extremely vulnerable protein, and the green point represents an interaction involving an extremely vulnerable protein reported to be a prion protein (ERF2) [24-26].
Figure 5
Figure 5
(η - ν) correlation for human protein interactions. (a) The (η-ν) correlation for all Pfam-filtered human protein interactions. Red points represent interactions involving extremely vulnerable proteins (Additional data file 4). (b) The correlation over Pfam-filtered human protein interactions that involve only PDB-reported proteins. The red point represents an interaction containing an extremely vulnerable protein.
Figure 6
Figure 6
(η-disorder) correlation for yeast and human protein interactions. Correlation between η-parameter and percent predicted disorder (disorder content) of the most disordered domain for each of (a) the 1,354 Pfam-filtered protein-interaction pairs in yeast and (b) the 607 pairs in human.
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