Disorder Prediction Methods, Their Applicability to Different Protein Targets and Their Usefulness for Guiding Experimental Studies

Abstract

The role and function of a given protein is dependent on its structure. In recent years, however, numerous studies have highlighted the importance of unstructured, or disordered regions in governing a protein’s function. Disordered proteins have been found to play important roles in pivotal cellular functions, such as DNA binding and signalling cascades. Studying proteins with extended disordered regions is often problematic as they can be challenging to express, purify and crystallise. This means that interpretable experimental data on protein disorder is hard to generate. As a result, predictive computational tools have been developed with the aim of predicting the level and location of disorder within a protein. Currently, over 60 prediction servers exist, utilizing different methods for classifying disorder and different training sets. Here we review several good performing, publicly available prediction methods, comparing their application and discussing how disorder prediction servers can be used to aid the experimental solution of protein structure. The use of disorder prediction methods allows us to adopt a more targeted approach to experimental studies by accurately identifying the boundaries of ordered protein domains so that they may be investigated separately, thereby increasing the likelihood of their successful experimental solution.

How disordered is my protein and what is its disorder for? A guide through the “dark side” of the protein universe

“…67 Recognizing the presence of IDPRs in a query protein is becoming increasingly important. For instance, it facilitates functional annotation of proteins 68 and is vital for delineating protein domains amenable to structural determination [69][70][71][72] and for protein target selection; [73][74][75] the latter 2 are crucial for the most commonly used X-ray crystallography-based approach to protein structure determination. The field of protein intrinsic disorder has materialized when bioinformatics techniques were used to transform a set of anecdotal examples of structure-less biologically active proteins, originally thought to be interesting outliers of the protein realm, into a quickly growing and vital branch of protein science which has already shown the natural abundance of IDPs/IDPRs.…”

Common Functions of Disordered Proteins across Evolutionary Distant Organisms

“…Intrinsically disordered proteins (IDPs) and regions (IDRs) lack a well-defined and folded three-dimensional structure in the absence and/or presence of a binding partner. Disorder is a fundamental property of the proteome and can be robustly predicted from primary sequence relying on characteristic patterns of amino acid distribution and overall amino acid content [5,6]. This class of proteins operates largely outside the classic structure-function relationship, with their functionality to the stages that do not share the capacity for anhydrobiosis [50].…”

shiny-pred: a server for the prediction of protein disordered regions

“…Over 60 computational protein disorder prediction servers are currently available, although not all publicly. Methods can be classified in one of the following categories (Atkins et al, 2015): (i) Ab initio or sequence-based, (ii) clustering, (iii) template based, and (iv) meta or consensus.…”