Peptide Recognition Mechanisms of Eukaryotic Signaling Modules

AbstractThe Myc proto-oncogene family consists of three members, C-MYC, MYCN, and MYCL, which encodes the transcription factor c-Myc (hereafter Myc), N-Myc, and L-Myc, respectively. Myc protein orchestrates diverse physiological processes, including cell proliferation, differentiation, survival, and apoptosis. Myc modulates about 15% of the global transcriptome, and its deregulation rewires the cellular signaling modules inside tumor cells, thereby acquiring selective advantages. The deregulation of Myc occurs in >70% of human cancers, and is related to poor prognosis; hence, hyperactivated Myc oncoprotein has been proposed as an ideal drug target for decades. Nevertheless, no specific drug is currently available to directly target Myc, mainly because of its “undruggable” properties: lack of enzymatic pocket for conventional small molecules to bind; inaccessibility for antibody due to the predominant nucleus localization of Myc. Although the topic of targeting Myc has actively been reviewed in the past decades, exciting new progresses in this field keep emerging. In this review, after a comprehensive summarization of valuable sources for potential druggable targets of Myc-driven cancer, we also peer into the promising future of utilizing macropinocytosis to deliver peptides like Omomyc or antibody agents to intracellular compartment for cancer treatment.

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Structural Perspective on Ancient Neuropeptide Y-like System reveals Hallmark Features for Peptide Recognition and Receptor Activation

Journal of Molecular Biology ◽

10.1016/j.jmb.2021.166992 ◽

2021 ◽

Vol 433 (13) ◽

pp. 166992

Author(s):

Miron Mikhailowitsch Gershkovich ◽

Victoria Elisabeth Groß ◽

Oanh Vu ◽

Clara Tabea Schoeder ◽

Jens Meiler ◽

...

Keyword(s):

Neuropeptide Y ◽

Receptor Activation ◽

Peptide Recognition ◽

Structural Perspective

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Structures of designed armadillo-repeat proteins show propagation of inter-repeat interface effects

Acta Crystallographica Section D Structural Biology ◽

10.1107/s2059798315023116 ◽

2016 ◽

Vol 72 (1) ◽

pp. 168-175 ◽

Cited By ~ 7

Author(s):

Christian Reichen ◽

Chaithanya Madhurantakam ◽

Simon Hansen ◽

Markus G. Grütter ◽

Andreas Plückthun ◽

...

Keyword(s):

Second Generation ◽

Body Movement ◽

Recognition System ◽

Third Generation ◽

Peptide Recognition ◽

Repeat Proteins ◽

Peptide Binding Site ◽

Armadillo Repeat ◽

The Stability ◽

Interface Effects

The armadillo repeat serves as a scaffold for the development of modular peptide-recognition modules. In order to develop such a system, three crystal structures of designed armadillo-repeat proteins with third-generation N-caps (YIII-type), four or five internal repeats (M-type) and second-generation C-caps (AII-type) were determined at 1.8 Å (His-YIIIM4AII), 2.0 Å (His-YIIIM5AII) and 1.95 Å (YIIIM5AII) resolution and compared with those of variants with third-generation C-caps. All constructs are full consensus designs in which the internal repeats have exactly the same sequence, and hence identical conformations of the internal repeats are expected. The N-cap and internal repeats M1to M3are indeed extremely similar, but the comparison reveals structural differences in internal repeats M4and M5and the C-cap. These differences are caused by long-range effects of the C-cap, contacting molecules in the crystal, and the intrinsic design of the repeat. Unfortunately, the rigid-body movement of the C-terminal part impairs the regular arrangement of internal repeats that forms the putative peptide-binding site. The second-generation C-cap improves the packing of buried residues and thereby the stability of the protein. These considerations are useful for future improvements of an armadillo-repeat-based peptide-recognition system.

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Prostaglandin E Receptor Subtypes EP2 and EP4 Promote TH1 Cell Differentiation and TH17 Cell Expansion Through Different Signaling Modules

Inflammation Research ◽

10.1007/bf03354229 ◽

2009 ◽

Vol 58 (S2) ◽

pp. S244-S248 ◽

Cited By ~ 1

Author(s):

Daiji Sakata ◽

Chengcan Yao ◽

Yoshiyasu Esaki ◽

Youxian Li ◽

Toshiyuki Matsuoka ◽

...

Keyword(s):

Cell Differentiation ◽

Cell Expansion ◽

Th17 Cell ◽

Prostaglandin E ◽

Receptor Subtypes ◽

Th1 Cell ◽

Signaling Modules

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Immunodominant-Peptide Recognition: Beta Testing TCRαβ

Immunity ◽

10.1016/j.immuni.2008.01.007 ◽

2008 ◽

Vol 28 (2) ◽

pp. 139-141 ◽

Cited By ~ 3

Author(s):

Jia-huai Wang ◽

Robert J. Mallis ◽

Ellis L. Reinherz

Keyword(s):

Peptide Recognition ◽

Beta Testing

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Cellular Differentiation in Response to Nutrient Availability: The Repressor of Meiosis, Rme1p, Positively Regulates Invasive Growth in Saccharomyces cerevisiae

Genetics ◽

10.1093/genetics/165.3.1045 ◽

2003 ◽

Vol 165 (3) ◽

pp. 1045-1058

Author(s):

Dewald van Dyk ◽

Guy Hansson ◽

Isak S Pretorius ◽

Florian F Bauer

Keyword(s):

Saccharomyces Cerevisiae ◽

Cellular Differentiation ◽

Promoter Sequence ◽

Quiescent State ◽

Invasive Growth ◽

Limited Growth ◽

Yeast Saccharomyces Cerevisiae ◽

A Cell ◽

Signaling Modules ◽

Differentiation Pathways

Abstract In the yeast Saccharomyces cerevisiae, the transition from a nutrient-rich to a nutrient-limited growth medium typically leads to the implementation of a cellular adaptation program that results in invasive growth and/or the formation of pseudohyphae. Complete depletion of essential nutrients, on the other hand, leads either to entry into a nonbudding, metabolically quiescent state referred to as G0 in haploid strains or to meiosis and sporulation in diploids. Entry into meiosis is repressed by the transcriptional regulator Rme1p, a zinc-finger-containing DNA-binding protein. In this article, we show that Rme1p positively regulates invasive growth and starch metabolism in both haploid and diploid strains by directly modifying the transcription of the FLO11 (also known as MUC1) and STA2 genes, which encode a cell wall-associated protein essential for invasive growth and a starch-degrading glucoamylase, respectively. Genetic evidence suggests that Rme1p functions independently of identified signaling modules that regulate invasive growth and of other transcription factors that regulate FLO11 and that the activation of FLO11 is dependent on the presence of a promoter sequence that shows significant homology to identified Rme1p response elements (RREs). The data suggest that Rme1p functions as a central switch between different cellular differentiation pathways.

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Foot scales in the Early Cretaceous bird Gansus from China provide evidences on the evolution of avian scales

10.21203/rs.3.rs-917342/v1 ◽

2021 ◽

Author(s):

Tao Zhao ◽

Zhiheng Li ◽

He Zhang ◽

Yanhong Pan

Keyword(s):

Signaling Pathway ◽

Early Cretaceous ◽

Fossil Record ◽

The Other ◽

Signaling Modules

Abstract Most modern birds have scales covering the foot, while our knowledge of early avian scales is limited, mainly due to the scarcity of fossil record. Here we characterize the morphological details of two types of scales preserved in IVPP V15077, a referred specimen of the Early Cretaceous bird Gansus. The scutellate and interstitial scales, which, in combination with previous discovery of scutate and reticulate scales in other Early Cretaceous birds, indicates that all four types present in modern birds have appeared in the Early Cretaceous. A phylogenetic context of fossilized scales suggests that the evolution of reticulate scales is conservative while that of the other types is more variable. It is consistent with the molecular hypothesis of the scales in modern birds and reptiles that most integumentary structures in amniotes are homologous with modified signaling modules to form various integumentary phenotypes, among which the reticulate scales may use the conserved signaling pathway.

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Deciphering and engineering chromodomain-methyllysine peptide recognition

Science Advances ◽

10.1126/sciadv.aau1447 ◽

2018 ◽

Vol 4 (11) ◽

pp. eaau1447 ◽

Cited By ~ 3

Author(s):

Ryan Hard ◽

Nan Li ◽

Wei He ◽

Brian Ross ◽

Gary C. H. Mo ◽

...

Keyword(s):

Protein Interactions ◽

Posttranslational Modifications ◽

Large Scale ◽

Regulation Of Gene Expression ◽

Live Cells ◽

Lysine Methylation ◽

Dynamic Regulation ◽

Peptide Recognition ◽

Protein Functions ◽

Domain Peptide

Posttranslational modifications (PTMs) play critical roles in regulating protein functions and mediating protein-protein interactions. An important PTM is lysine methylation that orchestrates chromatin modifications and regulates functions of non-histone proteins. Methyllysine peptides are bound by modular domains, of which chromodomains are representative. Here, we conducted the first large-scale study of chromodomains in the human proteome interacting with both histone and non-histone methyllysine peptides. We observed significant degenerate binding between chromodomains and histone peptides, i.e., different histone sites can be recognized by the same set of chromodomains, and different chromodomains can share similar binding profiles to individual histone sites. Such degenerate binding is not dictated by amino acid sequence or PTM motif but rather rooted in the physiochemical properties defined by the PTMs on the histone peptides. This molecular mechanism is confirmed by the accurate prediction of the binding specificity using a computational model that captures the structural and energetic patterns of the domain-peptide interaction. To further illustrate the power and accuracy of our model, we used it to effectively engineer an exceptionally strong H3K9me3-binding chromodomain and to label H3K9me3 in live cells. This study presents a systematic approach to deciphering domain-peptide recognition and reveals a general principle by which histone modifications are interpreted by reader proteins, leading to dynamic regulation of gene expression and other biological processes.

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