Structural mechanism of Myb–MuvB assembly

Guiley, Keelan Z.; Iness, Audra N.; Saini, Siddharth; Tripathi, Sarvind; Lipsick, Joseph S.; Litovchick, Larisa; Rubin, Seth M.

doi:10.1073/pnas.1808136115

Cited by 35 publications

(79 citation statements)

References 39 publications

(56 reference statements)

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“…The interaction was specific, as demonstrated by the loss of the PLA signal upon siRNA-mediated depletion of B-MYB ( Figure 4A,B). YAP also interacted with LIN9, a core subunit of the MuvB complex that is required for binding of B-MYB to MuvB (Guiley et al, 2018), providing further evidence for an interaction between YAP and MMB in cardiomyocytes.…”

Section: Yap Interacts With Mmb In Cardiomyocytesmentioning

confidence: 76%

Interaction of YAP with the Myb-MuvB (MMB) complex defines a transcriptional program to promote the proliferation of cardiomyocytes

Gründl

Walz

Hauf

et al. 2019

Preprint

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YAP, a major downstream effector of the Hippo signaling pathway, is an important regulator of cell proliferation. The ability of YAP to regulate G2/M gene expression is dependent on the Myb-MuvB (MMB) complex, consisting of the evolutionary MuvB core complex and the facultative B-MYB subunit, a transcription factor. Here we show that YAP directly binds to B-MYB. Disruption of the YAP/B-MYB interaction by overexpression of the YAP binding domain of B-MYB results in errors in cell division. We also show that YAP and MMB interact in vivo in the developing heart. Genome studies revealed that YAP and MMB regulate an overlapping set of cell cycle genes in cardiomyocytes. Cardiac specific deletion of the LIN9 subunit of MMB prevents the upregulation of cell cycle genes and the increased proliferation of cardiomyocytes lacking the Hippo-signaling component SAV1. Similarly, we find that proliferation of postnatal cardiomyocytes induced by constitutive active YAP depends on MMB. Our findings provide new insights in the YAP induced proliferation of cardiomyocytes through the functional interaction with MMB.

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Section: Yap Interacts With Mmb In Cardiomyocytesmentioning

confidence: 76%

Interaction of YAP with the Myb-MuvB (MMB) complex defines a transcriptional program to promote the proliferation of cardiomyocytes

Gründl

Walz

Hauf

et al. 2019

Preprint

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“…The high degree of sequence conservation in the MuvB-binding domains of vertebrate c-Myb proteins also led to the prediction that this domain would bind to the Myb-binding domain of LIN9-LIN52. However, this prediction was not borne out 45 . This surprising result highlights the need to test hypotheses based on molecular evolution analyses by direct experimentation.…”

Section: Discussionmentioning

confidence: 95%

“…The KW and DQ double alanine substitution mutants of Drosophila Myb were previously shown to abolish detectable immunoprecipitation of the Drosophila MuvB core complex from cell extracts in vitro and to be greatly diminished in rescuing expression of G2/M phase genes, cell cycle progression, and adult viability in vivo in Myb null mutant flies 11 . Similar mutants of the human B-Myb protein were subsequently shown to inhibit its physical interaction with the human LIN9-LIN52 Myb-binding domain complex 45 . The KW mutant of Drosophila Myb resembled the C-terminal Myb transgene in causing an approximately 10% incidence of the synMuv phenotype when in combination with a lin-15A mutation Drosophila ( Figure 6).…”

Section: Expression Of Drosophila Myb In C Elegans Causes a Synthetimentioning

confidence: 93%

“…Furthermore, conserved amino acids in Drosophila Myb (K606, W607, D617, Q618) that were previously shown to mediate biochemical interactions with the Drosophila MuvB core complex in vitro and to be required for the function of Drosophila Myb in vivo are predicted to contact C. elegans LIN9 and LIN52 11 . The homologous amino acids in human B-Myb were shown to contact human LIN9 and LIN52 in the crystallographic structure 45 .…”

Section: The Muvb-binding Domain Of Drosophila Myb Can Bind To a Nemamentioning

confidence: 99%

“…Although no sequenced species of Nematoda contains an animal-type Myb protein, they nevertheless do contain conserved Myb-binding domains in their LIN9 and LIN52 family proteins (Figures 1 and 3). Furthermore, the amino acids in the human LIN9 and LIN52 proteins that make direct contacts with human B-Myb in a structure determined by X-ray crystallography are well-conserved in the LIN9 and LIN52 proteins of the intensively studied nematode Caenorhabditis elegans 45 (Figure 3). Molecular modeling based on this structure predicts that the C. elegans LIN9 and LIN52 proteins are likely to be capable of binding to the MuvB-binding domain of Drosophila Myb (Figure 4).…”

Section: The Muvb-binding Domain Of Drosophila Myb Can Bind To a Nemamentioning

confidence: 99%

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A Long Lost Key Opens an Ancient Lock:DrosophilaMyb Causes a Synthetic Multivulval Phenotype in Nematodes

Vorster

Goetsch

Wijeratne

et al. 2019

Preprint

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ABSTRACTThe five-protein MuvB core complex (LIN9/Mip130, LIN37/Mip40, LIN52, LIN54/Mip120, and LIN53/p55CAF1/RBBP4) has been highly conserved during the evolution of animals. This nuclear complex interacts with proteins encoded by the RB tumor suppressor gene family and its associated E2F-DP transcription factors to form DREAM complexes that repress the expression of genes that regulate cell cycle progression and cell fate. The MuvB core complex also interacts with proteins encoded by the Myb oncogene family to form the Myb-MuvB complexes that activate many of the same target genes. We show that animal-type Myb genes and proteins are present in Bilateria, Cnidaria, and Placozoa, the latter including some of the simplest known animal species. However, bilaterian nematode worms appear to have lost their animal-type Myb genes hundreds of millions of years ago. Nevertheless, the amino acids in the LIN9 and LIN52 proteins that directly interact with the MuvB-binding domains of human B-Myb and Drosophila Myb are conserved in C. elegans. Here we show that, despite greater than 500 million years since their last common ancestor, the Drosophila melanogaster Myb protein can bind to the nematode LIN9 and LIN52 family proteins in vitro and can cause a synthetic multivulval (synMuv) phenotype in vivo. This phenotype is similar to that caused by loss-of-function mutations in C. elegans synMuvB class genes including those that encode homologs of the MuvB core, RB, E2F, and DP. Furthermore, amino acid substitutions in the MuvB-binding domain of Drosophila Myb that disrupt its functions in vitro and in vivo also disrupt its activity in C. elegans. We speculate that nematodes and other animals may contain another protein that can bind to LIN9 and LIN52 in order to activate transcription of genes repressed by DREAM complexes.

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Intramolecular interaction of B‐MYB is regulated through Ser‐577 phosphorylation

2020

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The transcription factor B-MYB is an important regulator of cell cycle-related processes that is activated by step-wise phosphorylation of multiple sites by cyclin-dependent kinases (CDKs) and conformational changes induced by the peptidylprolyl cis/trans isomerase Pin1. Here, we show that a conserved amino acid sequence around Ser-577 in the C-terminal part of B-MYB is able to interact with the B-MYB DNA-binding domain. Phosphorylation of Ser-577 disrupts this interaction and is regulated by the interplay of CDKs and the phosphatase CDC14B. Deletion of sequences surrounding Ser-577 hyperactivates the transactivation potential of B-MYB, decreases its proteolytic stability, and causes cell cycle defects. Overall, we show for the first time that B-MYB can undergo an intramolecular interaction that is controlled by the phosphorylation state of Ser-577.

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Structural mechanism of Myb–MuvB assembly

Cited by 35 publications

References 39 publications

Interaction of YAP with the Myb-MuvB (MMB) complex defines a transcriptional program to promote the proliferation of cardiomyocytes

Interaction of YAP with the Myb-MuvB (MMB) complex defines a transcriptional program to promote the proliferation of cardiomyocytes

A Long Lost Key Opens an Ancient Lock:DrosophilaMyb Causes a Synthetic Multivulval Phenotype in Nematodes

Intramolecular interaction of B‐MYB is regulated through Ser‐577 phosphorylation

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