Intrinsic Disorder in Human Proteins Encoded by Core Duplicon Gene Families

Abstract

Segmental duplications (i.e., highly homologous DNA fragments greater than 1 kb in length that are present within a genome at more than one site) are typically found in genome regions that are prone to rearrangements. A noticeable fraction of the human genome (∼5%) includes segmental duplications (or duplicons) that are assumed to play a number of vital roles in human evolution, human-specific adaptation, and genomic instability. Despite their importance for crucial events such as synaptogenesis, neuronal migration, and neocortical expansion, these segmental duplications continue to be rather poorly characterized. Of particular interest are the core duplicon gene (CDG) families, which are replicates sharing common “core” DNA among the randomly attached pieces and which expand along single chromosomes and might harbor newly acquired protein domains. Another important feature of proteins encoded by CDG families is their multifunctionality. Although it seems that these proteins might possess many characteristic features of intrinsically disordered proteins, to the best of our knowledge, a systematic investigation of the intrinsic disorder predisposition of the proteins encoded by core duplicon gene families has not been conducted yet. To fill this gap and to determine the degree to which these proteins might be affected by intrinsic disorder, we analyzed a set of human proteins encoded by the members of 10 core duplicon gene families, such as NBPF, RGPD, GUSBP, PMS2P, SPATA31, TRIM51, GOLGA8, NPIP, TBC1D3, and LRRC37. Our analysis revealed that the vast majority of these proteins are highly disordered, with their disordered regions often being utilized as means for the protein–protein interactions and/or targeted for numerous posttranslational modifications of different nature.

Rapid prediction and analysis of protein intrinsic disorder

“…We previously developed a web-crawler style disorder predictor for internal usage that was implemented into a tool we refer to as Disorder Spider (DiSpi) in our previous studies, see for example, refs. [34][35][36][37][38][39] DiSpi works by first aggregating disorder profiles from six well-known disorder predictors: PONDR VLXT, 40 PONDR VL3, 41 PONDR VLS2B, 42 PONDR-FIT, 43 IUPred-Short, and IUPred-Long. 44 Then, a mean disorder profile (MDP) is computed along with the standard error.…”

“…However, with a few exceptions, 32,33 these servers are not designed with genome‐scale structural bioinformatics or comparative genomics/proteomics in mind. We previously developed a web‐crawler style disorder predictor for internal usage that was implemented into a tool we refer to as Disorder Spider (DiSpi) in our previous studies, see for example, refs 34–39 . DiSpi works by first aggregating disorder profiles from six well‐known disorder predictors: PONDR VLXT, 40 PONDR VL3, 41 PONDR VLS2B, 42 PONDR‐FIT, 43 IUPred‐Short, and IUPred‐Long 44 .…”

Uniquome: Construction and Decoding of a Novel Proteomic Atlas that Contains New Peptide Entities

“…Remarkably, we identified 113 unreviewed proteins containing NPIP-specific FUPs, with 91 being related to NPIP family and 22 lacking known functions, presumably derived from, hitherto, uncharacterized and novel genes, strongly suggesting the expansion of NPIP family with 22 additional protein members (Table 2A). Given the critical contribution of nuclear pore complex abnormalities to neurodegenerative diseases (18), the 22, putative new NPIP (Nuclear Pore Complex-Interacting Protein) family members, may prove to play essential roles in Alzheimer’s and Huntington pathologies (17, 19).…”

Independent expansion, selection and hypervariability of theTBC1D3gene family in humans

“…This signature is potentially consistent with recent neofunctionalization and diversification of this gene family in humans. It is interesting that a recent analysis of the putative protein structure encoded by 10 of the core duplicons, including TBC1D3, are enriched for disordered regions that may enhance protein-protein interactions or post-translational modification (Bibber et al 2020).…”