Intrinsic Disorder as a Natural Preservative: High Levels of Intrinsic Disorder in Proteins Found in the 2600-Year-Old Human Brain

SIMPLE SUMMARY: Reported earlier, results of the proteomic analysis of the Heslington brain (which is at least 2600-year-old brain tissue uncovered within the skull excavated in 2008 from a pit in Heslington, Yorkshire, England) revealed the preservation of many proteins. Five of these proteins—heavy, medium, and light neurofilament proteins, glial fibrillary acidic protein, and myelin basic protein—are all engaged in the formation of non-amyloid protein aggregates, such as intermediate filaments and myelin sheath. Our bioinformatics analysis reported in this study revealed that these five proteins, their interactors, and many other proteins found in the Heslington brain are characterized by high level of intrinsic disorder, suggesting that intrinsic disorder might play a role in preserving brain tissue, likely by acting as a molecular mortar or cement that glues together various brain proteins and rigidifies the resulting assemblies, thereby generating highly stable matter. ABSTRACT: Proteomic analysis revealed the preservation of many proteins in the Heslington brain (which is at least 2600-year-old brain tissue uncovered within the skull excavated in 2008 from a pit in Heslington, Yorkshire, England). Five of these proteins—“main proteins”: heavy, medium, and light neurofilament proteins (NFH, NFM, and NFL), glial fibrillary acidic protein (GFAP), and myelin basic (MBP) protein—are engaged in the formation of non-amyloid protein aggregates, such as intermediate filaments and myelin sheath. We used a wide spectrum of bioinformatics tools to evaluate the prevalence of functional disorder in several related sets of proteins, such as the main proteins and their 44 interactors, all other proteins identified in the Heslington brain, as well as the entire human proteome (20,317 manually curated proteins), and 10,611 brain proteins. These analyses revealed that all five main proteins, half of their interactors and almost one third of the Heslington brain proteins are expected to be mostly disordered. Furthermore, most of the remaining Heslington brain proteins are expected to contain sizable levels of disorder. This is contrary to the expected substantial (if not complete) elimination of the disordered proteins from the Heslington brain. Therefore, it seems that the intrinsic disorder of NFH, NFM, NFL, GFAP, and MBP, their interactors, and many other proteins might play a crucial role in preserving the Heslington brain by forming tightly folded brain protein aggregates, in which different parts are glued together via the disorder-to-order transitions.