Architecture of the human interactome defines protein communities and disease networks

Abstract

The physiology of a cell can be viewed as the product of thousands of proteins acting in concert to shape the cellular response. Coordination is achieved in part through networks of protein-protein interactions that assemble functionally related proteins into complexes, organelles, and signal transduction pathways. Understanding the architecture of the human proteome has the potential to inform cellular, structural, and evolutionary mechanisms and is critical to elucidation of how genome variation contributes to disease1–3. Here, we present BioPlex 2.0 (Biophysical Interactions of ORFEOME-derived complexes), which employs robust affinity purification-mass spectrometry (AP-MS) methodology4 to elucidate protein interaction networks and co-complexes nucleated by more than 25% of protein coding genes from the human genome, and constitutes the largest such network to date. With >56,000 candidate interactions, BioPlex 2.0 contains >29,000 previously unknown co-associations and provides functional insights into hundreds of poorly characterized proteins while enhancing network-based analyses of domain associations, subcellular localization, and co-complex formation. Unsupervised Markov clustering (MCL)5 of interacting proteins identified more than 1300 protein communities representing diverse cellular activities. Genes essential for cell fitness6,7 are enriched within 53 communities representing central cellular functions. Moreover, we identified 442 communities associated with more than 2000 disease annotations, placing numerous candidate disease genes into a cellular framework. BioPlex 2.0 exceeds previous experimentally derived interaction networks in depth and breadth, and will be a valuable resource for exploring the biology of incompletely characterized proteins and for elucidating larger-scale patterns of proteome organization.

Regulation of the Hippo Pathway Transcription Factor TEAD

“…Further studies are needed to validate the physiological and functional significance of the difference in YAP-TEAD and TAZ-TEAD complexes. However, human interactome studies show interaction between TEADs, suggesting that homo- and hetero- complexes may differentially regulate TEAD transcriptional activity [31, 32]. As TEAD is the major transcriptional partner of YAP/TAZ [27, 33, 34], Hippo-regulated YAP/TAZ nuclear-cytoplasmic shuttling has served as a proxy for regulation of TEAD activity.…”

Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes

“…We observed a decrease in BRG1 and BAF60A staining in GBAF fractions 11-13, but not complete loss of staining. We hypothesized that this was due to the presence of the predicted GLTSCR1 paralog, GLTSCR1L (now referred to as BICRAL for clarity), which has also been detected in BAF subunit IP mass spectrometry studies as KIAA0240 (28,29). GLTSCR1 and BICRAL share 32% sequence homology (21% identity) and both contain a well-conserved "GLTSCR1" domain, which is also conserved between GLTSCR1 orthologs predicted in all multicellular organisms (Fig 3B).…”

“…GLTSCR1 has been identified in previous proteomic analyses of the SWI/SNF chromatin remodeling complex (18,(27)(28)(29) but has never been validated or characterized as a BAF complex subunit. After screening multiple commercially available antibodies against GLTSCR1, we identified an antibody that stained a band in the predicted region of 180 kDa using immunoblot analysis.…”

The Effect of Recombinant Human Erythropoietin on Bacterial Growth: A Dual-Edged Sword

“…material, see www.karger.com/doi/10.1159/000493684). EPO interacts with EPOR (quantitative score: 0.97) and GINM1 (Glycoprotein integral membrane 1; quantitative score: 0.79) [9]. In UniProt, using the search term “glycoprotein integral membrane protein in e coli,” 4 proteins were identified, one of which was adhesin (uniport id: Q47692).…”