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

Bioinformatics methods for studying the structure and function of intrinsically disordered proteins
The concept of protein disorder

Peter Tompa

Intrinsically disordered Proteins¹ (IDPs) exist and function without a fixed 3D Structure, challenging the classic structure-function paradigm. Mounting evidence indicates that they play crucial roles in Cell signaling and METABOLISM/31.html">Transcription regulation, particularly in eukaryotes. Using a wide range of biophysical techniques, structural disorder has been demonstrated in approximately 500 proteins, and their functional Classification has been built upon various scheme-based studies. Indirect evidence suggests that structural disorder is widespread: the human proteome alone contains several thousand proteins with pronounced structural disorder. To bridge the gap between known and putative IDPs, a variety of bioinformatics algorithms have been developed to reliably predict disordered states in proteins based on Amino Acid Sequence analysis. Attempts have also been made to predict IDP Functions, albeit with considerably less success. Because this protein group has evolved rapidly and their function typically relies on short motifs, the number of sequence fragments enabling the recognition of IDP functions remains rather limited. In this chapter, we provide a Brief Overview of the field of IDP research, focusing in particular on their functions and the bioinformatics tools designed to predict IDP Structure and function. Potential future directions for research in this area are also proposed and discussed.

Peter Tompa

Institute of Enzymology, Biological Research Center,

Hungarian Academy of Sciences,

1518 Budapest, Hungary

e-mail: tompa@enzim.hu

¹ As with many other terms, there is currently no universally accepted English equivalent for the term “intrinsically disordered proteins” [Note: adapted for the English Translation].

The core Concept of the classical paradigm linking protein function to a stable Spatial Structure has been widely and successfully applied to interpret the functions of Enzymes, receptors, and structural proteins. Decades of efforts to determine protein structures and recent research programs in structural Genomics have resulted in 50,000 high-quality structures currently deposited in the Protein Data Bank (PDB) (www.pdb.org), which has only reinforced traditional views in the field. However, recent evidence showing that many proteins or their individual regions lack a readily definable spatial structure under native, physiological conditions has challenged the universality of this paradigm (Tompa 2002, 2005; Dyson and Wright 2005; Uversky et al. 2005). With the rapid accumulation of data supporting this new alternative view of proteins, the need to reassess and expand the structure-function paradigm has become undeniable (Wright and Dyson 1999).

Using a range of biophysical techniques—primarily X-ray crystallography, NMR spectroscopy, small-angle X-ray scattering, and circular dichroism—it has been demonstrated that intrinsically disordered proteins (IDPs) or specific intrinsically disordered regions (IDRs) within proteins do not adopt a single, well-defined conformation. Instead, they exist as a fluctuating ensemble of various structural states (Tóth-Petróczy et al. 2002, 2005; Dyson and Wright 2005; Uversky et al. 2005). At first glance, they resemble the denatured state of Globular proteins. However, detailed structural analysis reveals that different IDPs can populate a wide range of conformational states—from fully disordered coils to compact molten globules—characterized by specific distributions of transient secondary and tertiary contacts (Uversky et al. 2000; Uversky 2002). Unlike denatured globular proteins, the functions of IDPs are a direct consequence of their disordered state and are predominantly associated with signaling regulation and Gene transcription processes (Iakoucheva et al. 2002; Ward et al. 2004; Tompa et al. 2006). Functional classification schemes for IDPs are based either on functions that directly arise from disorder or on transient versus permanent binding to partner molecules (Dunker et al. 2002; Tompa 2002, 2005).

IDPs are able not only to function despite lacking a stable structure, but structural disorder actually provides functional advantages in regulatory roles, such as the decoupling of binding Specificity and affinity (Wright and Dyson 1999), adaptability to diverse partners (Tompa et al. 2005), increased interaction rates (Pontius 1993), and frequent involvement in post-translational modifications (Iakoucheva et al. 2004). These advantages enable IDPs to occupy unique functional niches and explain the evolutionary success of protein disorder, with a critical difference in frequency between eukaryotes and prokaryotes (Iakoucheva et al. 2002; Ward et al. 2004; Tompa et al. 2006). They also account for the high level of disorder in functionally important regulatory proteins that play a major role in The Development of diseases, such as prion proteins (Lopez Garcia et al. 2000), BRCA1 (Mark et al. 2005), tau protein (Schweers et al. 1994), p53 (Bell et al. 2002), and α-synuclein (Weinreb et al. 1996). The most comprehensive collection of IDPs to date, the DisProt database (www.disprot.org), contains about 500 disordered proteins discovered predominantly by chance (Sickmeier et al. 2007). However, predictive Methods based on such protein collections suggest that approximately 5-15% of proteins in multicellular proteomes are entirely unstructured, and 30-50% contain at least one long disordered region (Iakoucheva et al. 2002; Ward et al. 2004; Tompa et al. 2006). To bridge this significant gap in knowledge, considerable effort is being devoted to developing bioinformatics algorithms capable of predicting disorder and function from amino acid sequence analysis. This review focuses on the principles and recent advances in The Study of IDPs.