Tissue specificity and the human protein interaction network

Abstract

A protein interaction network describes a set of physical associations that can occur between proteins. However, within any particular cell or tissue only a subset of proteins is expressed and so only a subset of interactions can occur. Integrating interaction and expression data, we analyze here this interplay between protein expression and physical interactions in humans. Proteins only expressed in restricted cell types, like recently evolved proteins, make few physical interactions. Most tissue-specific proteins do, however, bind to universally expressed proteins, and so can function by recruiting or modifying core cellular processes. Conversely, most 'housekeeping' proteins that are expressed in all cells also make highly tissue-specific protein interactions. These results suggest a model for the evolution of tissue-specific biology, and show that most, and possibly all, 'housekeeping' proteins actually have important tissue-specific molecular interactions.

Figure 1

Tissue-specific and recently evolved proteins make few protein interactions. (A) Integrating protein interaction and expression data to construct ‘local' interactomes for human cells and tissues. (B, C) The relationship between protein interaction degree and protein expression breadth (the number of tissues in which a protein is expressed) for the complete human protein interaction network (B), and (C) for ancestral (pre-metazoan) proteins (blue) and for metazoan-specific proteins (red). P<10e−15 in all cases, Kolmogorov–Smirnov test. Bars indicate one standard error. Interaction degree is the maximum number of co-expressed interaction partners. The same analysis is performed for the multiple-support network and for a network without protein complex-derived interactions in Supplementary Figure 1.

Figure 2

Most tissue-specific proteins interact with core cellular components, and most housekeeping proteins have tissue-specific physical interactions. (A) The proportion of the most tissue-specific proteins (proteins expressed in only 1–10/79 tissues) that interact with universally expressed housekeeping proteins. (B) The percentage of housekeeping proteins that interact with non-housekeeping proteins. These data are for the complete network. The same analysis is shown for the high-confidence multiple-support network in Supplementary Figure 2. Housekeeping proteins are defined by 10 criteria: (1) this study 79/79 tissues, (2) this study 71–79 tissues, (3) this study 79/79 tissues with reduced expression stringency, (4) this study 71–79 tissues with reduced stringency, (5) this study 79/79 tissues with increased stringency, (6) this study 71–79 tissues with increased stringency, (7) Zhu et al microarray data 18/18 tissues, (8) Zhu et al microarray data 16–18 tissues, (9) Zhu et al EST data 18/18 tissues, (10) Zhu et al EST data 16–18 tissues (Zhu et al, 2008). (C) Many proteins make interactions that can only occur in a subset of the tissues in which they are expressed. The number of tissues in which the interactions of a protein can occur is compared with the number of tissues in which a protein is expressed for proteins falling into each of the eight bins of tissue specificity. Data are shown for the complete network. Data for the filtered multiple-support network and reduced and increased stringency expression thresholds are shown in Supplementary Figure 3.

Figure 3

The re-use of housekeeping proteins for tissue-specific functions. Here we use the example of neurotransmitter receptor protein complexes identified by affinity purification followed by mass spectrometry (Pocklington et al, 2006). (A) A section of the binary protein interaction network of neurotransmitter receptor complexes, with subunits marked as universally expressed (housekeeping) proteins (yellow) and non-housekeeping (blue). The housekeeping and non-housekeeping interaction partners of the housekeeping protein Rac1 are highlighted and labeled as examples. (B) The percentage of subunits of neurotransmitter receptor protein complexes considered as universally expressed housekeeping proteins is shown for 10 different criteria of housekeeping proteins, as described in Figure 2. Criteria10 is used in panel A. (C) The proportion of these housekeeping subunits that have been experimentally verified as essential for learning and memory in mouse models or that are implicated in psychiatric disease in humans is shown for the same 10 criteria of housekeeping proteins. Protein complex subunits, binary protein–protein interactions, and genetic data are all from Pocklington et al (2006). The network in (A) was visualized using Biolayout Express (3D) (Freeman et al, 2007).