Research Article The interactome of CCT complex – A computational analysis Narayanan Aswathy, Dileep Pullepu, M. Anaul Kabir* Molecular Genetics Laboratory, School of Biotechnology, National Institute of Technology Calicut, Calicut 673601, Kerala, India A R T I C L E I N F O Article history: Received 10 February 2016 Received in revised form 8 July 2016 Accepted 5 September 2016 Available online 6 September 2016 Keywords: Chaperonin Interactome CCT WD-repeat H. sapiens S. cereviae A B S T R A C T The eukaryotic chaperonin, CCT (Chaperonin Containing TCP1 or TriC-TCP-1 Ring Complex) has been subjected to physical and genetic analyses in S. cerevisiae which can be extrapolated to human CCT (hCCT), owing to its structural and functional similarities with yeast CCT (yCCT). Studies on hCCT and its interactome acquire an additional dimension, as it has been implicated in several disease conditions like neurodegeneration and cancer. We attempt to study its stress response role in general, which will be reflected in the aspects of human diseases and yeast physiology, through computational analysis of the interactome. Towards consolidating and analysing the interactome data, we prepared and compared the unique CCT-interacting protein lists for S. cerevisiae and H. sapiens, performed GO term classification and enrichment studies which provide information on the diversity in CCT interactome, in terms of protein classes in the data set. Enrichment with disease-associated proteins and pathways highlight the medical importance of CCT. Different analyses converge, suggesting the significance of WD-repeat proteins, protein kinases and cytoskeletal proteins in the interactome. The prevalence of proteasomal subunits and ribosomal proteins suggest a possible cross-talk between protein-synthesis, folding and degradation machinery. A network of chaperones and chaperonins that function in combination can also be envisaged from the CCT interactome-Hsp70 interactome analysis. ã 2016 Elsevier Ltd. All rights reserved. 1. Introduction The proper three-dimensional structure of a protein is indispensable for its function. Protein folding is thus an important cellular event, in which several enzymes, regulators and special- ised machinery take part. Chaperones and chaperonins constitute the protein-folding machinery. CCT (Chaperonin Containing TCP1 or TriC-TCP-1 Ring Complex) are eukaryotic chaperonin complexes, hetero-oligomeric in structure, made up of two rings stacked back- to -back, enclosing a cavity where proteins fold as ATP binds to the complex. They are grouped together with the archaeal thermo- somes while the bacterial and organellar chaperonins constitute a separate group (reviewed by Hartl, 1996; Horwich et al., 2007). Defects in protein folding have been implicated in many medical conditions. Protein misfolding and subsequent aggrega- tion are clinical features of several neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease and Huntington’s disease (Ross and Poirier, 2004). The major substrates of CCT are proteins with high beta sheet propensity, which is a characteristic of misfolded proteins in neurodegenerative disorders (reviewed by Broadley and Hartl, 2009). CCT is found to be directly linked to polyQ protein disorders. Huntingtin (Htt) was identified as a substrate of CCT, with which it interacts in a subunit-specific manner. Deficiency of CCT6 increased the aggregate formation and over-expression of CCT1 inhibited aggregation (Tam et al., 2006). Impairment of CCT function was found to enhance toxicity due to Htt aggregation, while its over-expression suppressed the aggre- gation, when analysed in a yeast model (Behrends et al., 2006) suggesting that deficiency of CCT may be a potential cause of neurodegenerative diseases. The TriC subunits are underexpressed in the foetal brains of Down’s syndrome patients, an AD-related disease (Yoo et al., 2001). Defects in CCT have been implicated in other disease conditions as well. The disruption of CCT activity affects rod outer segment morphogenesis which in turn leads to retinal degeneration (Posokhova et al., 2011). Mutation in CCT5 (A492G) resulting in the substitution of a highly conserved histidine with arginine leads to autosomal recessive mutilating sensory neuropathy (Bouhouche et al., 2006). Mutation in CCT4 (G1349A) causes hereditary sensory neuropathy (Lee et al., 2003). The role of CCT in cancer has also been investigated (Boudiaf-Benmammar et al., 2013; Yokota et al., 2001). Yeast CCT and human CCT, made up of eight subunits (Cct1p- Cct8p), are structurally and functionally similar. Yeast CCT has been * Corresponding author. E-mail address: anaulk@nitc.ac.in (M. A. Kabir). http://dx.doi.org/10.1016/j.compbiolchem.2016.09.002 1476-9271/ã 2016 Elsevier Ltd. All rights reserved. Computational Biology and Chemistry 64 (2016) 396–402 Contents lists available at ScienceDirect Computational Biology and Chemistry journal homepa ge: www.elsev ier.com/locate/compbiolchem