From Protein Structure to Function with Bioinformatics.pdf

5 Structure and Function of Intrinsically Disordered Proteins 125enzymatic modifications require flexible and structurally adaptable regions inproteins, as shown by limited proteolysis, which occurs in linker regions in globularproteins (Fontana et al. 1997). Phosphorylation (Iakoucheva et al. 2004), ubiquitination(Cox et al. 2002) and deacetylation (Khan and Lewis 2005) also preferentiallyoccur in locally disordered regions. The general correlation of disorder withsuch sites has been demonstrated by predicting disorder in proteins that containshort recognition elements (also known as linear motifs (Puntervoll et al. 2003) ).It was found that linear motifs preferentially reside in locally disordered sequentialenvironments within the parent protein (Fuxreiter et al. 2007).Another category of IDPs functioning by transient binding is chaperones, assuggested in a statistical analysis on the level of disorder in protein- and RNAchaperones (Tompa and Csermely 2004). RNA chaperones have a very high proportionof disorder (40% of their residues fall into long disordered regions), andprotein chaperones also tend to be among the most disordered proteins (15% oftheir residues are located within long disordered regions). Because disorderedregions are often directly involved in chaperone function, an “entropy transfer”model of structural disorder in chaperone function could be formulated (Tompa andCsermely 2004). Implications of this model are verified by recent observations offully disordered chaperone proteins (Kovacs et al. 2008).5.4.2.3 Functions by Permanent BindingIn the other four categories IDPs/IDRs function by permanent partner binding.Proteins termed effectors bind and modify the activity of their partner, primarily anenzyme (Tompa 2002). Several IDPs characterized in great detail, such as p27Kip1,the inhibitor of Cdks (Kriwacki et al. 1996; Lacy et al. 2004), securin, the inhibitor ofseparase (Waizenegger et al. 2002) and calpastatin, the inhibitor of calpain (Kiss et al.2008a, b), belong here. Interestingly, such effectors sometimes have the potential toboth inhibit and activate their partners, as shown for p27Kip1 (Olashaw et al. 2004),or the C fragment of DHPR II–III loop (Haarmann et al. 2003). These and other observationshave led to the concept of the involvement of structural disorder in multiple,sometimes opposing, activities of proteins, i.e. moonlighting (Tompa et al. 2005).The next category of IDPs functioning by permanent partner binding is that ofassemblers, which either target the activity of attached domains, or assemble multiproteincomplexes (Tompa 2002). A high level of disorder in some scaffolding proteins,such as BRCA1 and Ste5 (Mark et al. 2005; Bhattacharyya et al. 2006), anincreased level of disorder in hub proteins of the interactome (Dosztanyi et al.2006; Haynes et al. 2006; Patil and Nakamura 2006), and the correlation of theaverage level of disorder with the number of partners in multi-protein complexes(Hegyi et al. 2007) attest to the generality of this relation.In the third class within this category, scavengers, there are disordered proteinswhich store and/or neutralize small ligand molecules. Milk nutrient casein(s), forexample, also function as calcium phosphate stores in milk, enabling a high totalcalcium phosphate concentration (Holt et al. 1996).