Abstract
Intrinsically disordered proteins (IDPs) and regions of intrinsic disorder (IDRs) are abundant in proteomes and are essential for many biological processes. Thus, they are often implicated in disease mechanisms, including neurodegeneration and cancer. The flexible nature of IDPs and IDRs provides many advantages, including (but not limited to) overcoming steric restrictions in binding, facilitating posttranslational modifications, and achieving high binding specificity with low affinity. IDPs adopt a heterogeneous structural ensemble, in contrast to typical folded proteins, making it challenging to interrogate their structure using conventional tools. Structural mass spectrometry (MS) methods are playing an increasingly important role in characterizing the structure and function of IDPs and IDRs, enabled by advances in the design of instrumentation and the development of new workflows, including in native MS, ion mobility MS, top-down MS, hydrogen-deuterium exchange MS, crosslinking MS, and covalent labeling. Here, we describe the advantages of these methods that make them ideal to study IDPs and highlight recent applications where these tools have underpinned new insights into IDP structure and function that would be difficult to elucidate using other methods.
Highlights
Interrogating the structure–function relationship of proteins and protein complexes has long been a productive area of scientific research, contributing to our understanding of biological processes and disease mechanisms and to the development of therapies
A further advantage of disorder is that it economizes genome and protein resources, as the interface of an Intrinsically disordered proteins (IDPs) in a protein–protein complex is similar to that formed between ordered proteins but consists of fewer residues from the disordered partner (Liu and Huang 2014)
This study demonstrates the suitability of studying preferred protein conformations with native MS (nMS), the agreement of nMS with solution phase small angle X-ray scattering (SAXS) measurements, and the complementarity of nMS
Summary
Interrogating the structure–function relationship of proteins and protein complexes has long been a productive area of scientific research, contributing to our understanding of biological processes and disease mechanisms and to the development of therapies. It was previously accepted that each protein has a specific three-dimensional conformation, composed of an intricate arrangement of secondary structure elements such as α-helices and β-sheets that dictates its function. It has emerged that not all proteins have a single specific conformation in their native state, and instead, they interconvert between multiple transient conformations, ranging from compact to extended, unhindered by energetic constraints (Wright and Dyson 2015) Such proteins, termed intrinsically disordered proteins (IDPs), are highly prevalent in biology, with bioinformatics studies indicating that the eukaryotic proteome is ∼20% disordered, with 36% of eukaryotic proteins containing >20% disorder and 12% carrying >50% disorder (Oldfield et al, 2005; Peng et al, 2015)
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