Protein Structure and Function. Application of Bioinformatics Methods - John Rigden 2014

Bioinformatics Methods for Studying the Structure and Functions of Disordered Proteins
Functional Classification of IDPs
Classification of IDPs Based on Mechanism of Action

In another system that accounts for the MOLECULAR MECHANISMS OF IDP action, intrinsically disordered Proteins are classified into one of five (Tompa 2002) and subsequently six (Tompa 2005) categories. In recent studies, prion proteins were added as an independent category (Pierce et al. 2005). This Classification scheme (Table 5.2) accommodates all currently known mechanisms of IDP/IDR action (Sickmeier et al. 2007).

Class="center">Table 5.2. IDP classification scheme. The classification of IDPs comprises seven functional categories based on their Molecular Mechanism of action. Two Examples are provided for each category, indicating the partner (if applicable) and the actual cellular function of the protein.

5.4.2.1. Entropic chains

The first functional category, unique to intrinsically disordered proteins, comprises entropic chains, whose function does not rely on partner recognition but stems directly from structural disorder. This class is further divided into subcategories: entropic springs, bristles/spacers, linkers, and steering devices. Their core Mechanisms of action are best described as influencing the spatial arrangement of attached domains or generating forces that oppose movements/structural changes (Dunker et al. 2002). The most thoroughly documented examples in this category include the entropic gating mechanism of the nuclear pore complex mediated by disordered NUP regions (Eibaum 2006), the entropic spacer/bristle function of protruding domains in microtubule-associated cytoskeletal proteins (Mukhopadhyay and Hoh 2001), and the entropic spring action of the titin PEVK region, which provides passive resting Muscle tension through elasticity (Trombitas et al. 1998).

5.4.2.2. Function via transient binding

In the remaining six categories, IDPs function through Molecular recognition, meaning that IDPs bind temporarily or permanently to one or more macromolecules or small ligands. Display sites serve primarily as platforms for post-translational modifications. For instance, enzymatic modifications require structurally flexible and easily adaptable protein regions, as demonstrated by Limited proteolysis occurring within the linker regions of Globular proteins (Fontana et al. 1997). Phosphorylation (Iakoucheva et al. 2004), ubiquitination (Cox et al. 2002), and deacetylation (Khan and Lewis 2005) are also prevalent in locally disordered regions. A general correlation between structural disorder and the presence of such sites has been established through Structure/76.html">Disorder Prediction in proteins containing short recognition elements, also known as linear motifs (Puntervoll et al. 2003). It has been shown that linear motifs in proteins are predominantly located within the vicinity of regions featuring local sequence disorder (Fuxreiter et al. 2007).

Chaperones represent another category of IDPs that function through transient binding. This has been demonstrated through statistical analyses of disorder levels in Protein and RNA chaperones (Tompa and Csermely 2004). The proportion of disorder in RNA chaperones is remarkably high, with 40% of residues located within extended disordered regions. Protein chaperones are also among the most disordered proteins, housing 15% of their residues in extensive disordered regions. The presence of disordered regions is often directly linked to chaperone function, leading to the "Entropy transfer" model, which captures The Role of structural disorder in chaperone activity (Tompa and Csermely 2004). The core tenets of this model have been supported by recent studies on fully disordered protein chaperones (Kovacs et al. 2008).

5.4.2.3. Function via permanent binding

In the remaining four categories, IDPs/IDRs function through permanent binding to a partner molecule. Proteins known as effectors bind to partner molecules—primarily Enzymes—and modulate their activity (Tompa 2002). This group includes several well-characterized IDPs, such as p27Kipl, a cyclin-dependent kinase inhibitor (Kriwacki et al. 1996; Lacy et al. 2004); securin, a separase inhibitor (Waizenegger et al. 2002); and calpastatin, a calpain inhibitor (Kiss et al. 2008a, b). Interestingly, such effectors can sometimes both inhibit and activate partner molecules, as demonstrated for p27Kipl (Olashaw et al. 2004) or the DHPR II-III loop C fragment (Haarmann et al. 2003). These and other findings have led to the concept that structural disorder elements contribute to multiple distinct, and sometimes opposing, Protein Functions, a phenomenon known as moonlighting (Tompa et al. 2005).

The next category of IDPs functioning through permanent partner binding comprises assemblers, which either regulate The activity of attached domains or assemble multi-Protein Complexes (Tompa 2002). The high degree of disorder observed in certain apoptosis-related proteins, such as BRCA1 and Ste5 (Mark et al. 2005; Bhattacharyya et al. 2006), the elevated disorder levels in hub Proteins of the interactome (Dosztanyi et al. 2006; Haynes et al. 2006; Patil and Nakamura 2006), and the correlation between average disorder and the number of partner molecules in multi-protein complexes (Hegyi et al. 2007) all reinforce the generality of this relationship.

The third class within this category consists of scavengers, which comprise disordered proteins that store and/or neutralize small Ligand molecules. For example, casein, a major milk nutrient, functions partly as a calcium phosphate reservoir, ensuring a high overall concentration of calcium phosphate in milk (Holt et al. 1996).

The final functional category of IDPs—prions—was omitted from earlier classification schemes (Tompa 2002, 2005). Prions were traditionally viewed as pathogenic agents, largely due to their inadvertent association with mad cow disease (Prusiner 1998). However, numerous recent publications indicate that the autocatalytic conformational changes underlying the prion phenomenon also occur during normal physiological functions in Yeast proteins (Tuite and Koloteva-Levin 2004) and even higher organisms, such as *Drosophila melanogaster* (Si et al. 2003a, b; Fowler et al. 2007). Such prions contain disordered, glutamine/asparagine-rich prion domains (Pierce et al. 2005) that are primarily responsible for the autocatalytic conformational transition affecting the functions of neighboring domains.