Targeting the Human Cancer Pathway Protein Interaction Network by Structural Genomics

Abstract

Structural genomics provides an important approach for characterizing and understanding systems biology. As a step toward better integrating protein three-dimensional (3D) structural information in cancer systems biology, we have constructed a Human Cancer Pathway Protein Interaction Network (HCPIN) by analysis of several classical cancer-associated signaling pathways and their physical protein-protein interactions. Many well known cancer-associated proteins play central roles as "hubs" or "bottlenecks" in the HCPIN. At least half of HCPIN proteins are either directly associated with or interact with multiple signaling pathways. Although some 45% of residues in these proteins are in sequence segments that meet criteria sufficient for approximate homology modeling (Basic Local Alignment Search Tool (BLAST) E-value <10 ؊6 ), only ϳ20% of residues in these proteins are structurally covered using high accuracy homology modeling criteria (i.e. BLAST E-value <10 ؊6 and at least 80% sequence identity) or by actual experimental structures. The HCPIN Website provides a comprehensive description of this biomedically important multipathway network together with experimental and homology models of HCPIN proteins useful for cancer biology research. To complement and enrich cancer systems biology, the Northeast Structural Genomics Consortium is targeting >1000 human proteins and protein domains from the HCPIN for sample production and 3D structure determination. The long range goal of this effort is to provide a comprehensive 3D structurefunction database for human cancer-associated proteins and protein complexes in the context of their interaction networks. The network-based target selection (BioNet) approach described here is an example of a general strategy for targeting co-functioning proteins by structural genomics projects.

The ARID Family Transcription Factor Bright Is Required for both Hematopoietic Stem Cell and B Lineage Development

“…Overexpression in the most highly aggressive subset of human diffuse large-B cell lymphomas (AID-DLBCL) has further implicated Bright as a proto-oncogene (38). The structure of the ARID DNA binding domain of Bright was solved (31) as part of the Human Cancer Protein Interaction Network (HCPIN) human cancer biology theme project (21), whose goal is to provide a three-dimensional (3D) structure database of human cancer-associated proteins.…”

Practical applications of structural genomics technologies for mutagen research

“…Cancer has been previously characterized as a "systems biology disease" [36] and NESG investigators assert that structural genomics provides an important approach for understanding systems biology [37]. NESG investigators took advantage of the existing Human Protein Reference Database [38], protein-protein interaction databases [39] and extensive cancer biology literature to build their Human Cancer Pathway Protein Interaction Network (HCPIN) database [37].…”

“…NESG investigators took advantage of the existing Human Protein Reference Database [38], protein-protein interaction databases [39] and extensive cancer biology literature to build their Human Cancer Pathway Protein Interaction Network (HCPIN) database [37]. The HCPIN includes ~3000 proteins and their interactions [37]. Proteins in HCPIN that did not have good existing structure templates in the PDB and therefore could not be modeled well, >1000 proteins, were targeted for structure determination.…”

Creating a community resource for protein science

“…For example, it has been possible to describe the structures of the proteins expressed in a whole organism (Thermotoga maritima), 58 and there has been significant progress in our understanding of proteins involved in cancer. 59 Significantly, it is now possible to have a molecular description of entire pathways. Although it took 25 years, we now have structures of all the enzymes involved in the tricarboxylic acid cycle (Fig.…”