Prediction and Experimental Detection of Structural and Functional Motifs in Intrinsically Unfolded Proteins

Abstract

Intrinsically unstructured proteins (IUPs) or proteins with intrinsically unstructured regions (IURs) have quickly gained increasing interest within the biological community because of their significant presence in the human genome and their potential links to major pathologies such as cancer, neurodegeneration and diabetes (Tompa, 2005; Tompa & Fuxreiter, 2008). The terms IUPs and IURs designate proteins or protein regions intrinsically devoid of a well defined tertiary structure. The concept was introduced a few years ago in the scientific literature as a brand new idea, which would represent a family of proteins thought to have been previously ignored or unappreciated (Dunker et al., 2001; Wright & Dyson, 1999). However, as in many other examples in Science, the concept of IUPs is far from being new. In the 70s, it was universally accepted that what were known as ‘biologically active peptides’ had no intrinsic structure, often being too short to have a proper hydrophobic core. Peptides would/could however fold in a definite conformation upon interaction with a partner/receptor, thus having all the features of modern IUPs (Boesch et al., 1978). Hormones and opioid peptides are two among several of the best studied examples. The concept of intrinsic disorder and/or flexibility has now been extended to proteins and has deeply transformed our perception of the importance of protein dynamics as opposed to the static picture introduced by years of crystallographic studies. Even more important is the fact that accepting the existence of IUPs proposes a unique paradigm in which function can be directly linked to structural disorder rather than to a defined structure. IUPs have been classified in two broad categories. In the first family, IUP’s function is achieved through binding to one or several partner molecule(s) in a structurally adaptive process, which enables an exceptional plasticity in cellular responses. These proteins do not form a structure by themselves and are functionally inactive in the absence of a partner, but structure can be induced upon recognition of another molecule. When bound to a substrate, they are able to acquire a structure and become rigid, according to an induced-fit mechanism or to what has been recently generalized in the concept of ‘conformational fuzziness’ (Wright & Dyson, 2009). Macromolecular association rates have in fact been demonstrated to be highly enhanced by a relatively non-specific association enabled by flexible recognition segments. Molecular recognition occurring in this way has been