From Protein Structure to Function with Bioinformatics.pdf

126 P. TompaThe final functional category of IDPs is that of prions, not included in previousclassification schemes (Tompa 2002, 2005). Prions have been traditionally consideredas pathogens, mostly because of their causal association with “mad cow diseases”(Prusiner 1998). In a recent surge of papers, however, it has been shown thatthe autocatalytic conformational change underlying the prion phenomenon alsooccurs in the normal physiological functions of proteins of yeast (Tuite andKoloteva-Levin 2004), or even higher organisms, such as D. melanogaster (Si et al.2003a, b; Fowler et al. 2007). These prion proteins have disordered Q/N-rich priondomains (Pierce et al. 2005), primarily responsible for the autocatalytic conformationaltransition that has functional consequences on neighbouring domains.5.4.3 Function-Related Structural Elements in IDPsA special feature of the recognition functions of IDPs, that their transient structuralelements are involved in molecular recognition, is directly pertinent to predictingfunction from sequence. The presence of such elements, often discernible at thelevel of both sequence and structure, may be used in predicting function. Orderedproteins evolved a great variety of domains to contribute specialized recognitionfunctions (Pawson and Nash 2003; Seet et al. 2006), whereas their cognate partners,such as those of the SH3 domain (Hiroaki et al. 2001; Ferreon and Hilser 2004),14-3-3 domain (Busto and Iglesias 2006) or PTB domain (Obenauer et al. 2003),tend to be short motifs within flexible regions of proteins. There are several differentbut interconnected concepts involving such short motifs, emphasizing structuralor sequential aspects of their implication in function.5.4.3.1 Preformed Structural ElementsThe concept of preformed structural elements (PSEs) has arisen from the analysisof structures of IDPs in complex with their partners. The key question addressedwas if the local structure of an IDP in complex with its partner could bepredicted by secondary structure prediction algorithms (Fuxreiter et al. 2004).It was found that the accuracy of predicting these IDP secondary structuralelements is higher than that of predictions for their ordered partner proteins,which suggests that IDPs have a strong conformational preference for the conformationsattained in their bound states, i.e. they probably use elements forrecognition that are (partially) pre-formed in the solution state. This relation isstrongest for helices and is weakest for coils, and it has been corroborated bysolution NMR studies of several unbound IDPs, which sample a local structuresimilar to the bound state. Examples of such IDPs include the KID domain ofCREB (Radhakrishnan et al. 1998), the KID domain of Cdk inhibitor p27Kip2(Kriwacki et al. 1996; Lacy et al. 2004), and the trans-activator domain of tumorsuppressor p53 (Lee et al. 2000).