580 research outputs found
Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8
The PI3K-related kinase (PIKK) SMG1 monitors the progression of metazoan nonsense-mediated mRNA decay (NMD) by phosphorylating the RNA helicase UPF1. Previous work has shown that the activity of SMG1 is impaired by small molecule inhibitors, is reduced by the SMG1 interactors SMG8 and SMG9, and is downregulated by the so-called SMG1 insertion domain. However, the molecular basis for this complex regulatory network has remained elusive. Here, we present cryo-electron microscopy reconstructions of human SMG1-9 and SMG1-8-9 complexes bound to either a SMG1 inhibitor or a non-hydrolyzable ATP analog at overall resolutions ranging from 2.8 to 3.6 angstrom. These structures reveal the basis with which a small molecule inhibitor preferentially targets SMG1 over other PIKKs. By comparison with our previously reported substrate-bound structure (Langer et al.,2020), we show that the SMG1 insertion domain can exert an autoinhibitory function by directly blocking the substrate-binding path as well as overall access to the SMG1 kinase active site. Together with biochemical analysis, our data indicate that SMG1 autoinhibition is stabilized by the presence of SMG8. Our results explain the specific inhibition of SMG1 by an ATP-competitive small molecule, provide insights into regulation of its kinase activity within the NMD pathway, and expand the understanding of PIKK regulatory mechanisms in general.Acknowledgements: Daniel Bollschweiler and Tillman Schäfer at the MPIB cryo-EM facility for help with EM data collection and Barbara Steigenberger and Elisabeth Weyher at MPIB biochemistry core facility for carrying out mass spectrometry
Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity
PI3K-related kinases (PIKKs) are large Serine/Threonine (Ser/Thr)-protein kinases central to the regulation of many fundamental cellular processes. PIKK family member SMG1 orchestrates progression of an RNA quality control pathway, termed nonsense-mediated mRNA decay (NMD), by phosphorylating the NMD factor UPF1. Phosphorylation of UPF1 occurs in its unstructured N- and C-terminal regions at Serine/Threonine-Glutamine (SQ) motifs. How SMG1 and other PIKKs specifically recognize SQ motifs has remained unclear. Here, we present a cryo-electron microscopy (cryo-EM) reconstruction of a human SMG1-8-9 kinase complex bound to a UPF1 phosphorylation site at an overall resolution of 2.9 angstrom. This structure provides the first snapshot of a human PIKK with a substrate-bound active site. Together with biochemical assays, it rationalizes how SMG1 and perhaps other PIKKs specifically phosphorylate Ser/Thr-containing motifs with a glutamine residue at position +1 and a hydrophobic residue at position -1, thus elucidating the molecular basis for phosphorylation site recognition
Scotland, Catalonia and the “right” to self-determination: a comment suggested by Kathryn Crameri’s “Do Catalans Have the Right to Decide?
No abstract available
Muon Spin Relaxation and Susceptibility Studies of Pure and Doped Spin 1/2 Kagom\'{e}-like system (CuZn)VO(OH) 2HO
Muon spin relaxation (SR) and magnetic susceptibility measurements have
been performed on the pure and diluted spin 1/2 kagom\'{e} system
(CuZn)VO(OH) 2HO. In the pure
system we found a slowing down of Cu spin fluctuations with decreasing
temperature towards K, followed by slow and nearly
temperature-independent spin fluctuations persisting down to = 50 mK,
indicative of quantum fluctuations. No indication of static spin freezing was
detected in either of the pure (=1.0) or diluted samples. The observed
magnitude of fluctuating fields indicates that the slow spin fluctuations
represent an intrinsic property of kagom\'e network rather than impurity spins.Comment: 4 pges, 4 color figures, Phys. Rev. Lett. in pres
Doping and temperature dependence of electron spectrum and quasiparticle dispersion in doped bilayer cuprates
Within the t-t'-J model, the electron spectrum and quasiparticle dispersion
in doped bilayer cuprates in the normal state are discussed by considering the
bilayer interaction. It is shown that the bilayer interaction splits the
electron spectrum of doped bilayer cuprates into the bonding and antibonding
components around the point. The differentiation between the bonding
and antibonding components is essential, which leads to two main flat bands
around the point below the Fermi energy. In analogy to the doped
single layer cuprates, the lowest energy states in doped bilayer cuprates are
located at the point. Our results also show that the striking
behavior of the electronic structure in doped bilayer cuprates is intriguingly
related to the bilayer interaction together with strong coupling between the
electron quasiparticles and collective magnetic excitations.Comment: 9 pages, 4 figures, updated references, added figures and
discussions, accepted for publication in Phys. Rev.
Site-Dilution in quasi one-dimensional antiferromagnet Sr2(Cu1-xPdx)O3: reduction of Neel Temperature and spatial distribution of ordered moment sizes
We investigate the Neel temperature of Sr2CuO3 as a function of the site
dilution at the Cu (S=1/2) sites with Pd (S=0), utilizing the muon spin
relaxation (muSR) technique. The Neel temperature, which is Tn=5.4K for the
undoped system, becomes significantly reduced for less than one percent of
doping Pd, giving a support for the previous proposal for the good
one-dimensionality. The Pd concentration dependence of the Neel temperature is
compared with a recent theoretical study (S. Eggert, I. Affleck and M.D.P.
Horton, Phys. Rev. Lett. 89, 47202 (2002)) of weakly coupled one-dimensional
antiferromagnetic chains of S=1/2 spins, and a quantitative agreement is found.
The inhomogeneity of the ordered moment sizes is characterized by the muSR time
spectra. We propose a model that the ordered moment size recovers away from the
dopant S=0 sites with a recovery length of \xi = 150-200 sites. The origin of
the finite recovery length \xi for the gapless S=1/2 antiferromagnetic chain is
compared to the estimate based on the effective staggered magnetic field from
the neighboring chains.Comment: 10 pages, 9 figures, submitted to PR
The Dynamical Behaviors in (2+1)-Dimensional Gross-Neveu Model with a Thirring Interaction
We analyze (2+1)-dimensional Gross-Neveu model with a Thirring interaction,
where a vector-vector type four-fermi interaction is on equal terms with a
scalar-scalar type one. The Dyson-Schwinger equation for fermion self-energy
function is constructed up to next-to-leading order in 1/N expansion. We
determine the critical surface which is the boundary between a broken phase and
an unbroken one in () space. It is observed that the
critical behavior is mainly controlled by Gross-Neveu coupling and
the region of the broken phase is separated into two parts by the line
. The mass function is strongly
dependent upon the flavor number N for , while weakly for
, the critical flavor number
increases as Thirring coupling decreases. By driving the CJT
effective potential, we show that the broken phase is energetically preferred
to the symmetric one. We discuss the gauge dependence of the mass function and
the ultra-violet property of the composite operators.Comment: 19 pages, LaTex, 6 ps figure files(uuencoded in seperate file
Phase separation and suppression of critical dynamics at quantum transitions of itinerant magnets: MnSi and (SrCa)RuO
Quantum phase transitions (QPTs) have been studied extensively in correlated
electron systems. Characterization of magnetism at QPTs has, however, been
limited by the volume-integrated feature of neutron and magnetization
measurements and by pressure uncertainties in NMR studies using powderized
specimens. Overcoming these limitations, we performed muon spin relaxation
(SR) measurements which have a unique sensitivity to volume fractions of
magnetically ordered and paramagnetic regions, and studied QPTs from itinerant
heli/ferro magnet to paramagnet in MnSi (single-crystal; varying pressure) and
(SrCa)RuO (ceramic specimens; varying ). Our results
provide the first clear evidence that both cases are associated with
spontaneous phase separation and suppression of dynamic critical behavior,
revealed a slow but dynamic character of the ``partial order'' diffuse spin
correlations in MnSi above the critical pressure, and, combined with other
known results in heavy-fermion and cuprate systems, suggest a possibility that
a majority of QPTs involve first-order transitions and/or phase separation.Comment: 11 pages, 4 figures, 21 authors, to appear in Nature Physic
Muon Spin Relaxation Studies of Magnetic-Field-Induced Effects in High- Superconductors
Muon spin relaxation (SR) measurements in high transverse magnetic
fields () revealed strong field-induced quasi-static
magnetism in the underdoped and Eu doped (La,Sr)CuO and
LaBaCuO, existing well above and . The
susceptibility-counterpart of Cu spin polarization, derived from the muon spin
relaxation rate, exhibits a divergent behavior towards K. No
field-induced magnetism was detected in overdoped
LaSrCuO, optimally doped Bi2212, and Zn-doped
YBaCuO.Comment: 4 pages, 4 color figure
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