| The intrinsically disordered proteins(IDPs)are proteins that lack a specific three-dimensional structure and their structures vary in different environments.In living organisms,especially eukaryotes,there is a wide range of intrinsic disordered proteins,which are involved in important signal transduction,biological regulation and other processes.IDPs are often the hubs of the interaction network.They perform very important functions.Protein domains are the basic units of protein structure,function and evolution.Protein domains usually have stable three-dimensional structures,while a few domains are disordered in the natural state.There have been many studies on the function of IDPs,but there is no systematic and comprehensive study on the distribution and function of features of intrinsically disordered domains(IDDs).Therefore,we firstly focused on the distribution and functional significance of the IDDs in 1870 representative species of archaea,bacteria and eukaryotes.As a result,there was a significant positive correlation between the percentage of IDDs and the complexity of species.However,there are also many exceptions: Halophiles and actinomycetes have lower biology complexity but they contain a higher percentage of IDDs.Compared with nematoda,ascomycetes are relatively simple but they have a higher percentage of IDDs.This result suggests that the percentage of IDDs in a species is not only related to the species complexity,but also to clade-specific functions.So,why do the percentages of IDDs vary greatly among species? This may be due to two aspects of the evolution of protein domains.First,some lineage-specific domains,especially in eukaryotes,tend to be disordered,resulting in a higher percentage of IDDs in these species.Secondly,the domains shared in different clades evolved different degrees of disorder,that is,the same domains may have significantly different domain structural disorder ratio(DSDR)in different species.The IDDs in prokaryotes and eukaryotes perform different types of biological functions.The IDDs in prokaryotes tend to localize at ribosomes and cytoplasm and participate in the synthesis and metabolism of macromolecules.In eukaryotes,IDDs tend to localize at the nucleus and participate in a variety of regulatory processes,including gene expression regulation,nuclear transport,RNA splicing,chromosome assembly and cytoskeletal assembly.The function of the IDD is mainly affected by domain age and the disordered width(the number of species where the domain is IDD).In addition,we found that the IDDs in metazoans and fungi have different disorder feature.Metazoans tend to have more IDDs with high disorder rate but no continuous disorder region(CDR),while fungi tend to have more IDDs with low disorder rate but CDR.This phenomenon may be related to their different functional requirements.The IDPs are wide expressed in different OTCs with generally low abundances.In different developmental stages,the IDPs are preferentially utilized.The widely expression and preferential utilization of the IDPs reflect their important roles in the development or adult OTCs.The IDPs have various functions and are usually involved in the regulation of related biological processes.Therefore,each life system needs more of them.In addition,the IDPs also tend to be expressed in specific OTCs,which may be related to the special functions of some OTCs.In general,the IDPs have flexible conformational features and play an important role in biological regulation and signal transduction.Intrinsic disorder is a unique structural feature,which makes IDPs have more interaction partners and participate in the formation of various interactions.Because they are important regulators of cell processes,they are strictly controlled.When the IDPs are incorrectly modified,mistranslated or abnormally expressed,they usually form promiscuous interactions,which is related to the occurrence of cancer,mental diseases,neurodegenerative disease,cardiovascular disease,diabetes and other diseases.We mainly focused on the relationship between the abnormal changes of protein disorder and the formation of cancer and mental diseases.With the advances in genomics,we have had a deeper understanding of the pathogenesis of cancer.Mutations in cancer can change the protein disorder,which may change the function of the protein and make it participate in important pathways related to the development of cancer.In this study,we found that in many cancers,the missense mutations of arginine(R)to tryptophan(W)or cysteine(C)and the nonsense mutations of the arginine(R),glutamate(E),and glutamine(Q)sites may change the protein disorder.The data of mutation on protein disorder provides important reference information for screening new tumor markers.Diffuse gastric cancer(DGC)is one of the most common malignant tumors in China,with a high mortality rate.In recent years,with the progress of proteomics,the pathogenesis of gastric cancer has been further revealed,but the problems in the diagnosis and treatment of DGC has not been completely solved.We explored the relationship between the intrinsical properties and the role of proteins in DGC from several aspects: domain number,domain age and domain structural disorder rate,etc.We found that IDPs tend to be usually up-regulated in DGC,suggesting that they may play an important role in the occurrence and development of DGC.The relationship between the upregulation of SOX9(an example of IDP)and the development of DGC has been clarified,but its mechanism has not been fully revealed.We speculate that after overexpression,the disordered protein SOX9 can bind to a variety of long-chain non-coding RNAs or other proteins and participate in the occurrence of tumors.Mental disorder is one of the central nervous system diseases.And its mechanism is not clear.Its symptoms are complex and characterized by disorder in cognization,emotion,behavior.And mental disorder accompanied by painful experience and functional impairment.The neurobiological mechanisms for the genes associated with mental disorders are still largely unknown.Based on the known genes related to mental disorders,a comprehensive exploration of its intrinsic properties can provide a regular understanding of the features of genes related to mental disorder and provide clues for in-depth exploration of the pathogenesis.The over-or under-representation analysis based on the hypergeometric distribution model was performed to determine the intrinsic properties of genes associated with mental disorders.Based on the analysis results,the probability of each human protein-coding gene participating in the occurrence of mental disorders was quantified.In combination with the differential expression data,new potential associated genes were screened.These results give valuable information for the pathogenesis study of mental disorders.In summary,this study comprehensively explored the distribution and functional features of IDDs at proteome-wide level among 1870 species,and systematically analyzed the reasons for the uneven distribution of IDDs in different species.This study firstly revealed the close relationship between the percentage of IDDs and the species complexity and the role of IDDs in the formation of lineage-specific functions.These results enrich our understanding of protein domain evolution and function and have important scientific significance.We further explore the role of IDPs in the development of diseases such as cancer and mental disorder,which provides important reference information for the studies of the mechanism and treatment of cancer and mental disorder. |
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