B56

Previous studies have shown that in addition to its role within the voltage-gated calcium channel complex in the plasma membrane, the neuronal CaV β subunit can translocate to the cell nucleus. However, little is known regarding the role this protein could play in the nucleus, nor the molecular mechanism used by CaV β to enter this cell compartment. This report shows evidence that CaV β3 has nuclear localization signals (NLS) that are not functional, suggesting that the protein does not use a classical nuclear import pathway...

An increasing number of mutations associated with devastating human diseases are diagnosed by whole-genome/exon sequencing. Recurrent de novo missense mutations have been discovered in B56δ (encoded by PPP2R5D ), a regulatory subunit of protein phosphatase 2A (PP2A), that cause intellectual disabilities (ID), macrocephaly, Parkinsonism, and a broad range of neurological symptoms. Single-particle cryo-EM structures show that the PP2A-B56δ holoenzyme possesses closed latent and open active forms. In the closed form, the long, disordered arms of B56δ termini fold against each other and the holoenzyme core, establishing dual autoinhibition of the phosphatase active site and the substrate-binding protein groove...

The cell cycle is key to life. After decades of research, it is unclear whether any parts of this process have yet to be identified. Fam72a is a poorly characterized gene and is evolutionarily conserved across multicellular organisms. Here, we have found that Fam72a is a cell-cycle-regulated gene that is transcriptionally and post-transcriptionally regulated by FoxM1 and APC/C, respectively. Functionally, Fam72a directly binds to tubulin and both the Aα and B56 subunits of PP2A-B56 to modulate tubulin and Mcl1 phosphorylation, which in turn affects the progression of the cell cycle and signaling of apoptosis...

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder. The pathogenesis of IBS has not yet been fully elucidated, and the relationship between human leukocyte antigen (HLA) class I molecules and IBS is not clear. The present case-control study investigated the correlation between HLA-A and HLA-B genes and IBS. Peripheral blood samples were collected from 102 IBS patients and 108 healthy volunteers at Nanning First People's Hospital. DNA was extracted using a routine procedure, and HLA-A and HLA-B gene polymorphisms were identified by polymerase chain reaction with sequence-specific primers to determine the genotype and distribution frequency of HLA-A and HLA-B in IBS patients and healthy controls...

The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56α is a human tumour suppressor. However, the molecular mechanisms inhibiting PP2A-B56α in cancer are poorly understood. Here, we report molecular level details and structural mechanisms of PP2A-B56α inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56α trimer, CIP2A displaces the PP2A-A subunit and thereby hijacks both the B56α, and the catalytic PP2Ac subunit to form a CIP2A-B56α-PP2Ac pseudotrimer. Further, CIP2A competes with B56α substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56α...

High-Grade Serous Carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP-inhibitors (PARPi) have become the mainstay of HGSC targeted therapy, given that these tumors are driven by a high degree of genomic instability and Homologous Recombination (HR) defects. Nonetheless, ~30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies...

Protein phosphatase 2 A (PP2A) is a major heterotrimeric serine/threonine protein phosphatase comprised of three subunits, including structural subunits (A), regulatory subunits (B), and catalytic subunits (C). PP2A has been widely shown to involve in a series of cell signal transduction processes such as cell metabolism, cell cycle regulation, DNA replication, gene transcription and protein translation in yeast and mammalian. However, the roles of PP2A in pathogenic fungi Magnaporthe oryzae still remain unclear...

The recent discovery of lanthanide-metal-decorated metallo-borospherenes LM3 B18 - (LM = La, Tb) marks the onset of a new class of boron-metal binary nanomaterials. Using the experimentally observed or theoretically predicted borospherenes as ligands and based on extensive first-principles theory calculations, we predict herein a series of novel chiral metallo-borospherenes C 2 Ni6 ∈ B39 - (1), C 1 Ni6 ∈ B41 + (3), C 2 Ni6 ∈ B42 2+ (4), C 2 Ni6 ∈ B42 (5), and C 2 Ni8 ∈ B56 (6) as the global minima of the systems decorated with quasi-planar heptacoordinate Ni (phNi) centers in η7 -B7 heptagons on the cage surfaces, which are found to be obviously better favoured in coordination energies than hexacoordinate Ni centers in previously reported D 2d Ni6 ∈ B40 (2)...

PP2A-related (neuro) developmental disorders are a family of genetic diseases caused by a heterozygous alteration in one of several genes encoding a subunit of type 2A protein phosphatases. Reported affected genes, so far, are PPP2R5D , encoding the PP2A regulatory B56δ subunit; PPP2R1A , encoding the scaffolding Aα subunit; and PPP2CA , encoding the catalytic Cα subunit-in that order of frequency. Patients with a pathogenic de novo mutation in one of these genes, in part, present with overlapping features, such as generalized hypotonia, intellectual and developmental delay, facial dysmorphologies, seizures, and autistic features, and, in part, with opposite features, e...

Venetoclax-combination therapies are becoming the standard-of-care in acute myeloid leukemia (AML). However, the therapeutic benefit of these drugs in older/unfit patients is limited to only a few months, highlighting the need for more effective therapies. PP2A is a tumor suppressor phosphatase with pleiotropic functions that becomes inactivated in ~70% of AML cases. PP2A promotes cancer cell death by modulating the phosphorylation state in a variety of proteins along the mitochondrial apoptotic pathway. We therefore hypothesized that pharmacological PP2A reactivation could increase BCL2 dependency in AML cells and thus potentiate venetoclax-induced cell death...

The Bub1 and BubR1 kinetochore proteins support proper chromosome segregation and mitotic checkpoint activity. Bub1 and BubR1 are paralogues with Bub1 being a kinase while BubR1 localizes the PP2A-B56 protein phosphatase to kinetochores in humans. Whether this spatial separation of kinase and phosphatase activity is important is unclear as some organisms integrate both activities into one Bub protein. Here we engineer human Bub1 and BubR1 proteins integrating kinase and phosphatase activities into one protein and show that these do not support normal mitotic progression...

Boron and boron-based nanoclusters exhibit unique structural and bonding patterns in chemistry. Extensive density functional theory calculations performed in this work predict the mononuclear walnut-like Ci C50 B54 (1) (C2 B10 @C48 B44 ), C1 C50 B54 (2) (CB11 @C49 B43 ), and S10 C50 B54 (3) (B12 @C50 B42 ) which contain one icosahedral-Cn B12-n core (n = 0, 1, 2) at the center following the Wade's skeletal electron counting rules and the approximately electron sufficient binuclear peanut-like Cs C88 B78 (4) ((C2 B10 )2 @C84 B58 ), Cs C88 B78 (5) ((CB11 )2 @C86 B56 ), Cs C88 B78 (6) ((B12 )2 @C88 B54 ), Cs B180 (7) ((B12 )2 @B156 ), Cs B182 (8) ((B12 )2 @B158 ), and Cs B184 (9) ((B12 )2 @B160 ) which encapsulate two interconnected Cn B12-n icosahedrons inside...

In eukaryotes, the spindle assembly checkpoint protects genome stability in mitosis by preventing chromosome segregation until incorrect microtubule-kinetochore attachment geometries have been eliminated and chromosome biorientation has been completed. These error correction and checkpoint processes are linked by the conserved Aurora B and MPS1 Ser/Thr kinases.1 , 2 MPS1-dependent checkpoint signaling is believed to be initiated by kinetochores without end-on microtubule attachments,3 , 4 including those generated by Aurora B-mediated error correction...

Hippo-Yorkie (Hpo-Yki) signaling is central to diverse developmental processes. While its redeployment has been amply demonstrated, its context-specific regulation remains poorly understood. The Drosophila eye disc is a continuous epithelium folded into two layers, the peripodial epithelium (PE) and the retinal progenitor epithelium. Here, Yki acts in the PE, first to promote PE identity by suppressing retina fate, and subsequently to maintain proper disc morphology. In the latter process, loss of Yki results in the displacement of a portion of the differentiating retinal epithelium onto the PE side...

Scaffold liprin-α1 is required to assemble dynamic plasma membrane-associated platforms (PMAPs) at the front of migrating breast cancer cells, to promote protrusion and invasion. We show that the N-terminal region of liprin-α1 contains an LxxIxE motif interacting with B56 regulatory subunits of serine/threonine protein phosphatase 2A (PP2A). The specific interaction of B56γ with liprin-α1 requires an intact motif, since two point mutations strongly reduce the interaction. B56γ mediates the interaction of liprin-α1 with the heterotrimeric PP2A holoenzyme...

Formation and stability of the B56 boron cluster were investigated using a topological approach and the disk aromaticity model. An extensive global energy minimum search for the B56 system which was carried out by means of the Mexican Enhanced Genetic Algorithm (MEGA) in conjunction with density functional theory computations, confirms a quasi-planar structure as its energetically most stable isomer. Such a structural motif is derived by applying a topological leapfrog operation to a B12 form. Its high thermodynamic stability can be explained by the disk aromaticity model in which the delocalization of its π orbitals can be assigned to the levels of a particle in a circular box with the [(1σ)2 (1π)4 (1δ)4 (1φ)4 (2σ)2 (1γ)4 (2π)4 (2δ)4 (1η)4 (2φ)4 (1θ)2 ] electronic configuration...

The canonical function of lentiviral Vif proteins is to counteract the mutagenic potential of APOBEC3 antiviral restriction factors. However, recent studies have discovered that Vif proteins from diverse HIV-1 and simian immunodeficiency virus (SIV) isolates degrade cellular B56 phosphoregulators to remodel the host phosphoproteome and induce G2/M cell cycle arrest. Here, we evaluate the conservation of this activity among non-primate lentiviral Vif proteins using fluorescence-based degradation assays and demonstrate that maedi-visna virus (MVV) Vif efficiently degrades all five B56 family members...

As a surveillance mechanism, the activated spindle assembly checkpoint (SAC) potently inhibits the E3 ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome) to ensure accurate chromosome segregation. Although the protein phosphatase 2A (PP2A) has been proposed to be both, directly and indirectly, involved in spindle assembly checkpoint inactivation in mammalian cells, whether it is similarly operating in the fission yeast Schizosaccharomycer pombe has never been demonstrated. Here, we investigated whether fission yeast PP2A is involved in SAC silencing by following the rate of cyclin B (Cdc13) destruction at SPBs during the recovery phase in nda3-KM311 cells released from the inhibition of APC/C by the activated spindle checkpoint...

Protein phosphatase 2A (PP2A) holoenzymes target broad substrates by recognizing short motifs via regulatory subunits. PP2A methylesterase 1 (PME-1) is a cancer-promoting enzyme and undergoes methylesterase activation upon binding to the PP2A core enzyme. Here, we showed that PME-1 readily demethylates different families of PP2A holoenzymes and blocks substrate recognition in vitro. The high-resolution cryoelectron microscopy structure of a PP2A-B56 holoenzyme-PME-1 complex reveals that PME-1 disordered regions, including a substrate-mimicking motif, tether to the B56 regulatory subunit at remote sites...

Depletion of the Anaphase-Promoting Complex/Cyclosome (APC/C) activator Cdc20 arrests cells in metaphase with high levels of the mitotic cyclin (Cyclin B) and the Separase inhibitor Securin. In mammalian cells this arrest has been exploited for the treatment of cancer with drugs that engage the spindle assembly checkpoint and, recently, with chemical inhibitors of the APC/C. While most cells arrested in mitosis for prolonged periods undergo apoptosis, others skip cytokinesis and enter G1 with unsegregated chromosomes...