title: The structural network of Interleukin-10 and its implications in inflammation and cancer.
abstract: BACKGROUND
  Inflammation has significant roles in all phases of tumor development, including initiation, progression and metastasis. Interleukin-10 (IL-10) is a well-known immuno-modulatory cytokine with an anti-inflammatory activity. Lack of IL-10 allows induction of pro-inflammatory cytokines and hinders anti-tumor immunity, thereby favoring tumor growth. The IL-10 network is among the most important paths linking cancer and inflammation. The simple node-and-edge network representation is useful, but limited, hampering the understanding of the mechanistic details of signaling pathways. Structural networks complete the missing parts, and provide details. The IL-10 structural network may shed light on the mechanisms through which disease-related mutations work and the pathogenesis of malignancies.
  
  
  RESULTS
  Using PRISM (a PRotein Interactions by Structural Matching tool), we constructed the structural network of IL-10, which includes its first and second degree protein neighbor interactions. We predicted the structures of complexes involved in these interactions, thereby enriching the available structural data. In order to reveal the significance of the interactions, we exploited mutations identified in cancer patients, mapping them onto key proteins of this network. We analyzed the effect of these mutations on the interactions, and demonstrated a relation between these and inflammation and cancer. Our results suggest that mutations that disrupt the interactions of IL-10 with its receptors (IL-10RA and IL-10RB) and α2-macroglobulin (A2M) may enhance inflammation and modulate anti-tumor immunity. Likewise, mutations that weaken the A2M-APP (amyloid precursor protein) association may increase the proliferative effect of APP through preventing β-amyloid degradation by the A2M receptor, and mutations that abolish the A2M-Kallikrein-13 (KLK13) interaction may lead to cell proliferation and metastasis through the destructive effect of KLK13 on the extracellular matrix.
  
  
  CONCLUSIONS
  Prediction of protein-protein interactions through structural matching can enrich the available cellular pathways. In addition, the structural data of protein complexes suggest how oncogenic mutations influence the interactions and explain their potential impact on IL-10 signaling in cancer and inflammation.
authors: Ece Saliha
authors: ES
authors: Acuner-Ozbabacan
authors: Billur Hatice
authors: BH
authors: Engin
authors: Emine
authors: E
authors: Guven-Maiorov
authors: Guray
authors: G
authors: Kuzu
authors: Serena
authors: S
authors: Muratcioglu
authors: Alper
authors: A
authors: Baspinar
authors: Zhong
authors: Z
authors: Chen
authors: Carter
authors: C
authors: Van Waes
authors: Attila
authors: A
authors: Gursoy
authors: Ozlem
authors: O
authors: Keskin
authors: Ruth
authors: R
authors: Nussinov
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D030562:Databases, Protein; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D016753:Interleukin-10 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053709:Interleukin-10 Receptor alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053710:Interleukin-10 Receptor beta Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016296:Mutagenesis; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013816:Thermodynamics; D000511:alpha-Macroglobulins / Q000378:metabolism
chemical_list: C578813:A2M protein, human; D016564:Amyloid beta-Protein Precursor; D053709:Interleukin-10 Receptor alpha Subunit; D053710:Interleukin-10 Receptor beta Subunit; D000511:alpha-Macroglobulins; D016753:Interleukin-10; D003546:Cysteine Endopeptidases; C063281:prorenin processing enzyme