The dark proteome of cancer: Intrinsic disorderedness and functionality of HIF-1α along with its interacting proteins

Abstract

The dark side of protein is the region (s) where molecular conformation is unknown. Intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) are the dark matter of biology due to inability to visualize them using standard structure elucidation technique such as X-ray crystallography due to lack in diffraction signal. IDPs are the functionally important class of proteins with entire protein or its parts lack ordered three-dimensional structure. Computational studies have predicted that nearly one-third of the human proteome is disordered, which gives the enormous flexibility and functional diversity to proteins. The conserved residues and elements in disordered proteins are critical for function and might be parts of peptide motifs or protein-protein interaction interfaces. For example, regions of proteins that are involved in disorder-based molecular recognition are known as molecular recognition features (MoRFs). Generally, MoRFs could undergo disorder to order transition or vice versa at interaction with specific partners. Hypoxia inducible factor 1α (HIF-1α) is a master transcriptional regulator involved in response to hypoxia, which is associated with many pathological conditions. Importantly, HIF-1α regulates various steps of cancer progression such as cell survival, tumor cell invasion, and metastasis. In this chapter, we have extensively analyzed the molecular recognition features and their relationship with disordered regions and associated structural islands of HIF-1α. We had also analyzed the disorderness and MoRFs of HIF-1α primary interaction partners that are enriched in IDPRs and MoRFs giving their role in protein-protein interaction and cancer regulation.

Keywords: Cancer; HIF-1α; Intrinsically disordered protein regions (IDPRs); Intrinsically disordered proteins (IDPs); Protein-protein interaction; Signaling.