A subset of functional adaptation mutations alter propensity for α-helical conformation in the intrinsically disordered glucocorticoid receptor tau1core activation domain

Salamanova, Evdokiya; Costeira-Paulo, Joana; Han, Kyou‐Hoon; Kim, Do Hyoung; Nilsson, Lennart; Wright, Anthony P. H.

doi:10.1016/j.bbagen.2018.03.015

Cited by 7 publications

(7 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent mutation studies on ACTR and p53TAD, this aspect was unambiguously verified where the degree of the pre-population of a PreSMo was shown to be critical for target binding [ 67 , 68 ]. In addition, either gain-of-function or loss-of-function mutants of hGR tau1core activation domain were all associated with mutations of PreSMo-forming residues, demonstrating the functional significance of PreSMos [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Transient Secondary Structures as General Target-Binding Motifs in Intrinsically Disordered Proteins

Kim¹,

Han²

2018

IJMS

Self Cite

View full text Add to dashboard Cite

Intrinsically disordered proteins (IDPs) are unorthodox proteins that do not form three-dimensional structures under non-denaturing conditions, but perform important biological functions. In addition, IDPs are associated with many critical diseases including cancers, neurodegenerative diseases, and viral diseases. Due to the generic name of “unstructured” proteins used for IDPs in the early days, the notion that IDPs would be completely unstructured down to the level of secondary structures has prevailed for a long time. During the last two decades, ample evidence has been accumulated showing that IDPs in their target-free state are pre-populated with transient secondary structures critical for target binding. Nevertheless, such a message did not seem to have reached with sufficient clarity to the IDP or protein science community largely because similar but different expressions were used to denote the fundamentally same phenomenon of presence of such transient secondary structures, which is not surprising for a quickly evolving field. Here, we summarize the critical roles that these transient secondary structures play for diverse functions of IDPs by describing how various expressions referring to transient secondary structures have been used in different contexts.

show abstract

Section: Discussionmentioning

confidence: 99%

Transient Secondary Structures as General Target-Binding Motifs in Intrinsically Disordered Proteins

Kim¹,

Han²

2018

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…There is consistent evidence that the MYC N-terminus is a conformationally disordered region and that conformational changes accompany interactions with partner proteins as part of a coupled binding and folding interaction mechanism [ 9 , 27 , 28 , 44 ]. Recently, the stability of protein regions with transient alpha-helical conformation has been shown to be an important modulator of activity for this kind of protein domain, see [ 45 ] and references therein, but neither T58A nor T58I is predicted to affect the transient alpha-helical region immediate N-terminal of T58. However, the Dynamine predictor of protein backbone dynamics predicts an increased backbone rigidity in the T58I mutant that is not seen for T58A, and the Anchor predictor predicts a greater reduction in protein interaction propensity for T58I than for T58A.…”

Section: Discussionmentioning

confidence: 99%

Differential Transcriptional Reprogramming by Wild Type and Lymphoma-Associated Mutant MYC Proteins as B-Cells Convert to a Lymphoma Phenotype

Mahani

Arvidsson

Sadeghi

et al. 2021

Cancers

View full text Add to dashboard Cite

The MYC transcription factor regulates a vast number of genes and is implicated in many human malignancies. In some hematological malignancies, MYC is frequently subject to missense mutations that enhance its transformation activity. Here, we use a novel murine cell system to (i) characterize the transcriptional effects of progressively increasing MYC levels as normal primary B-cells transform to lymphoma cells and (ii) determine how this gene regulation program is modified by lymphoma-associated MYC mutations (T58A and T58I) that enhance its transformation activity. Unlike many previous studies, the cell system exploits primary B-cells that are transduced to allow regulated MYC expression under circumstances where apoptosis and senescence pathways are abrogated by the over-expression of the Bcl-xL and BMI1 proteins. In such cells, transition from a normal to a lymphoma phenotype is directly dependent on the MYC expression level, without a requirement for secondary events that are normally required during MYC-driven oncogenic transformation. A generalized linear model approach allowed an integrated analysis of RNA sequencing data to identify regulated genes in relation to both progressively increasing MYC level and wild type or mutant status. Using this design, a total of 7569 regulated genes were identified, of which the majority (n = 7263) were regulated in response to progressively increased levels of wild type MYC, while a smaller number of genes (n = 917) were differentially regulated, compared to wild type MYC, in T58A MYC- and/or T58I MYC-expressing cells. Unlike most genes that are similarly regulated by both wild type and mutant MYC genes, the set of 917 genes did not significantly overlap with known lipopolysaccharide regulated genes, which represent genes regulated by MYC in normal B cells. The genes that were differently regulated in cells expressing mutant MYC proteins were significantly enriched in DNA replication and G2 phase to mitosis transition genes. Thus, mutants affecting MYC proteins may augment quantitative oncogenic effects on the expression of normal MYC-target genes with qualitative oncogenic effects, by which sets of cell cycle genes are abnormally targeted by MYC as B cells transition into lymphoma cells. The T58A and T58I mutations augment MYC-driven transformation by distinct mechanisms.

show abstract

“…[10] Consistently there is evidence that the MYC N-terminus is a conformationally disordered region and that conformational changes accompany interaction with partner proteins as part of a coupled binding and folding interaction mechanism. [9,26,44,45] Recently, the stability of protein regions with transient alpha-helical conformation has been shown to be an important modulator of activity for this kind of protein domain, see [46] and references therein, but neither T58A nor T58I is predicted to affect the transient alpha-helical region immediately N-terminal of T58. However, the Dynamine predictor of protein backbone dynamics predicts an increased backbone rigidity in the T58I mutant that is not seen for T58A and the ANCHOR predictor predicts a greater reduction in protein interaction propensity for T58I than for T58A.…”

Section: Discussionmentioning

confidence: 99%

Differential transcriptional reprogramming by wild type and lymphoma-associated mutant MYC proteins as B-cells convert to lymphoma-like cells

Mahani

Arvidsson

Sadeghi

et al. 2020

Preprint

View full text Add to dashboard Cite

The transcription factor MYC regulates the expression of a vast number of genes and is implicated in various human malignancies, for which it's deregulation by genomic events such as translocation or amplification can be either disease-defining or associated with poor prognosis. In hematological malignancies MYC is frequently subject to missense mutations and one such hot spot where mutations have led to increased protein stability and elevated transformation activity exists within its transactivation domain. Here we present and characterize a model system for studying the effects of gradually increasing MYC levels as B-cells progress to lymphoma-like cells. Inclusion of two frequent lymphoma-associated MYC mutants (T58A and T58I) allowed for discrimination of changes in the MYC regulatory program according to mutation status. Progressive increase in MYC levels significantly altered the transcript levels of 7569 genes and subsets of these were regulated differently in mutant MYC proteins compared to WT MYC or between the mutant MYC proteins. Functional classification of the differentially regulated genes based on expression levels across different MYC levels confirmed previously found MYC regulated functions such as ribosome biogenesis and purine metabolism while other functional groups such as the downregulation of genes involved in B-cell differentiation and chemotaxis were novel. Gene sets that were differently regulated in cells overexpressing mutant MYC proteins contained an over-representation of genes involved in DNA Replication and transition from the G2 phase to mitosis. The cell model presented here mimics changes seen during lymphoma development in the Eμ-Myc mouse model as well as MYC-dependent events associated with poor prognosis in a wide range of human cancer types and therefore constitutes a relevant cell model for in vitro mechanistic studies of wild type and mutant MYC proteins in relation to lymphoma development.

show abstract

A subset of functional adaptation mutations alter propensity for α-helical conformation in the intrinsically disordered glucocorticoid receptor tau1core activation domain

Cited by 7 publications

References 58 publications

Transient Secondary Structures as General Target-Binding Motifs in Intrinsically Disordered Proteins

Transient Secondary Structures as General Target-Binding Motifs in Intrinsically Disordered Proteins

Differential Transcriptional Reprogramming by Wild Type and Lymphoma-Associated Mutant MYC Proteins as B-Cells Convert to a Lymphoma Phenotype

Differential transcriptional reprogramming by wild type and lymphoma-associated mutant MYC proteins as B-cells convert to lymphoma-like cells

Contact Info

Product

Resources

About