Abstract：
:How calmodulin (CaM) acts in KRAS-driven cancers is a vastly important question. CaM binds to and stimulates PI3Kα/Akt signaling, promoting cell growth and proliferation. Phosphorylation of CaM at Tyr99 (pY99) enhances PI3Kα activation. PI3Kα is a lipid kinase. It phosphorylates PIP2 to produce PIP3, to which Akt binds. PI3Kα has two subunits: the regulatory p85 and the catalytic p110. Here, exploiting explicit-solvent MD simulations we unveil key interactions between phosphorylated CaM (pCaM) and the two SH2 domains in the p85 subunit, confirm experimental observations, and uncover PI3Kα's mechanism of activation. pCaMs form strong and stable interactions with both nSH2 and cSH2 domains, with pY99 being the dominant contributor. Despite the high structural similarity between the two SH2 domains, we observe that nSH2 prefers an extended CaM conformation, whereas cSH2 prefers a collapsed conformation. Notably, collapsed CaM is observed after binding of an extended CaM to K-Ras4B. Thus, the more populated extended pCaM conformation targets nSH2 to release its autoinhibition of p110 catalytic sites. This executes the key activation step of PI3Kα. Independently, K-Ras4B allosterically activates p110. These events are at the cell membrane, which contributes to tighten the PI3Kα Ras binding domain/K-Ras4B interaction, to accomplish K-Ras4B allosteric activation, with a minor contribution from cSH2.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Zhang M,Jang H,Gaponenko V,Nussinov Rdoi
10.1016/j.bpj.2017.09.008subject
Has Abstractpub_date
2017-11-07 00:00:00pages
1956-1967issue
9eissn
0006-3495issn
1542-0086pii
S0006-3495(17)31019-6journal_volume
113pub_type
杂志文章abstract：:The unfolding and folding of protein barnase has been extensively investigated in bulk conditions under the effect of denaturant and temperature. These experiments provided information about structural and kinetic features of both the native and the unfolded states of the protein, and debates about the possible existe...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/j.bpj.2015.11.015
更新日期：2016-01-05 00:00:00
abstract：:The relative contributions of the allosteric and affinity factors toward the change in p50 have been calculated for a series of effectors of hemoglobin (Hb). Shifts in the ligand affinity of deoxy Hb and the values for 50% ligand saturation (p50) were obtained from oxygen equilibrium data. Because the high-affinity pa...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/S0006-3495(90)82556-X
更新日期：1990-03-01 00:00:00
abstract：:The structure and dynamics of soluble misfolded aggregates are poorly understood, despite their importance in protein science and disease. Water-soluble self-associated species that do not become insoluble over time are invaluable tools for high-resolution conformational studies aimed at dissecting the determinants of...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/j.bpj.2010.12.3722
更新日期：2011-02-02 00:00:00
abstract：:Förster resonance energy transfer (FRET)-based biosensors for the quantitative analysis of intracellular signaling, including sensors for monitoring cyclic adenosine monophosphate (cAMP), are of increasing interest. The measurement of the donor/acceptor emission ratio in tandem biosensors excited at the donor excitati...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1529/biophysj.107.125666
更新日期：2008-12-01 00:00:00
abstract：:Fibrin polymerizes to produce branching fibers forming a three-dimensional network, which has been difficult to visualize by conventional microscopy. Three-dimensional images of whole clots at high resolution were obtained from stereo-pair intermediate-voltage electron micrographs. Computer software was developed to p...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/S0006-3495(95)80327-9
更新日期：1995-04-01 00:00:00
abstract：:In multicellular organisms, single-fluorophore imaging is obstructed by high background. To achieve a signal/noise ratio conducive to single-molecule imaging, we adapted reflected light-sheet microscopy (RLSM) to image highly opaque late-stage Drosophila embryos. Alignment steps were modified by means of commercially ...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/j.bpj.2015.12.035
更新日期：2016-02-23 00:00:00
abstract：:Halorhodopsin (HR), the light-driven chloride transport pigment of Halobacterium halobium, was bleached and reconstituted with retinal analogues with the pi electron system interrupted at different locations (dihydroretinals). The absorption maxima of the artificial pigments formed with the dihydroretinals are found t...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/S0006-3495(88)83080-7
更新日期：1988-02-01 00:00:00
abstract：:To detect changes in capsid structure that occur when a preassembled bacteriophage T7 capsid both packages and cleaves to mature-size longer (concatameric) DNA, the kinetics and thermodynamics are determined here for the binding of the protein-specific probe, 1,1'-bi(4-anilino)naphthalene-5,5'-di-sulfonic acid (bis-AN...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/S0006-3495(92)81724-1
更新日期：1992-11-01 00:00:00
abstract：:Endophilins are SH3- and BAR domain-containing proteins implicated in membrane remodeling and vesicle formation. Endophilins A1 and A2 promote the budding of endocytic vesicles from the plasma membrane, whereas endophilin B1 has been implicated in vesicle budding from intracellular organelles, including the trans-Golg...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/j.bpj.2016.06.017
更新日期：2016-08-09 00:00:00
abstract：:The cytoplasm of a living cell is a dynamic environment through which intracellular components must move and mix. In motile, rapidly deforming cells such as human neutrophils, bulk cytoplasmic flow couples cell deformation to the transport and dispersion of cytoplasmic particles. Using particle-tracking measurements i...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/j.bpj.2017.09.009
更新日期：2017-11-07 00:00:00
abstract：:K(ATP) channels are comprised of a pore-forming protein, Kir6.x, and the sulfonylurea receptor, SURx. Interaction of adenine nucleotides with Kir6.2 positively charged amino acids such as K185 and R201 on the C-terminus causes channel closure. Substitution of these amino acids with other positively charged residues ha...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/S0006-3495(03)74847-4
更新日期：2003-01-01 00:00:00
abstract：:A complete mechanistic understanding of membrane-localized processes in vesicular transport, such as membrane budding and fission, requires their reconstitution with biochemically-defined components from a biochemically-defined substrate. Supported bilayers formed by vesicle fusion represent an attractive substrate fo...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/j.bpj.2010.04.036
更新日期：2010-07-21 00:00:00
abstract：:The crystal structure of the RNA octamer, 5'-GGCGUGCC-3' has been determined from x-ray diffraction data to 1.5 angstroms resolution. In the crystal, this oligonucleotide forms five self-complementary double-helices in the asymmetric unit. Tandem 5'GU/3'UG basepairs comprise an internal loop in the middle of each dupl...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1529/biophysj.106.081018
更新日期：2006-06-15 00:00:00
abstract：:Homooligomerization of proline utilization A (PutA) bifunctional flavoenzymes is intimately tied to catalytic function and substrate channeling. PutA from Bradyrhizobium japonicum (BjPutA) is unique among PutAs in that it forms a tetramer in solution. Curiously, a dimeric BjPutA hot spot mutant was previously shown to...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/j.bpj.2018.04.046
更新日期：2018-06-19 00:00:00
abstract：:We used optical tweezers to analyze the effect of jasplakinolide and cyclodextrin on the force exerted by lamellipodia from developing growth cones (GCs) of isolated dorsal root ganglia (DRG) neurons. We found that 25 nM of jasplakinolide, which is known to inhibit actin filament turnover, reduced both the maximal exe...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/j.bpj.2012.04.036
更新日期：2012-06-06 00:00:00
abstract：:In the absence of atomic structures of high-density lipoproteins in their lipid-bound states, many molecular models have been produced based on experimental data. Using molecular dynamics, we show that a recently proposed "solar-flares" model of discoidal high-density lipoprotein is implausible. Our simulations show a...
journal_title：Biophysical journal
pub_type： 信件
doi：10.1529/biophysj.108.131581
更新日期：2008-06-01 00:00:00
abstract：:Fourier transform infrared (FTIR) spectroscopy was used to monitor secondary structural changes associated with binding of bovine prothrombin and prothrombin fragment 1 to acidic lipid membranes. Prothrombin and prothrombin fragment 1 were examined under four different conditions: in the presence of (a) Na2EDTA, (b) 5...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/S0006-3495(91)82031-8
更新日期：1991-07-01 00:00:00
abstract：:A simple method of generating electric field-induced concentration gradients in planar supported bilayers has been developed. Gradients of charged, fluorescently labeled probes were visualized by epifluorescence microscopy and could be observed at field strengths as low as 1 V/cm. Steady-state concentration gradients ...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/S0006-3495(95)80067-6
更新日期：1995-11-01 00:00:00
abstract：:Mutant Ras proteins are important drivers of human cancers, yet no approved drugs act directly on this difficult target. Over the last decade, the idea has emerged that oncogenic signaling can be diminished by molecules that drive Ras into orientations in which effector-binding interfaces are occluded by the cell memb...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/j.bpj.2019.12.039
更新日期：2020-03-10 00:00:00
abstract：:The opening and closing of the CFTR Cl- channel are regulated by ATP hydrolysis at its two nucleotide binding domains (NBDs). However, the mechanism and functional significance of ATP hydrolysis are unknown. Sequence similarity between the NBDs of CFTR and GTP-binding proteins suggested the NBDs might have a structure...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/S0006-3495(95)80113-X
更新日期：1995-12-01 00:00:00
abstract：:It is widely assumed that the decay of fluorescence in photosynthetic systems can be described as a sum of exponential components and that the amplitude of each component is directly related to the absorption cross-section of the antenna pigments coupled to the fluorescing species. We present exact calculations of exc...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/S0006-3495(89)82767-5
更新日期：1989-12-01 00:00:00
abstract：:We present a two-component coarse-grained molecular-dynamics model for simulating the erythrocyte membrane. The proposed model possesses the key feature of combing the lipid bilayer and the erythrocyte cytoskeleton, thus showing both the fluidic behavior of the lipid bilayer and the elastic properties of the erythrocy...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/j.bpj.2011.11.4012
更新日期：2012-01-04 00:00:00
abstract：:Rearrangement of tertiary structure in response to mechanical force (termed tertiary structure elasticity) in the tandem Ig chain is the first mode of elastic response for muscle protein titin. Tertiary structure elasticity occurs at low stretching forces (few tens of pN), and was described at atomic resolution in a r...
journal_title：Biophysical journal
pub_type： 信件
doi：10.1016/j.bpj.2011.01.019
更新日期：2011-02-16 00:00:00
abstract：:Solid-state NMR study shows that the 22-residue K3 peptide (Ser(20)-Lys(41)) from beta(2)-microglobulin (beta(2)m) adopts a beta-strand-loop-beta-strand conformation in its fibril state. Residue Pro(32) has a trans conformation in the fibril state of the peptide, while it adopts a cis conformation in the native state ...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1529/biophysj.107.125054
更新日期：2008-07-01 00:00:00
abstract：:A 15-ns molecular dynamics (MD) simulation of the fully hydrated dimyristoylphosphatidylcholine-cholesterol (DMPC-Chol) bilayer in the liquid-crystalline state was carried out to investigate the effect of Chol on the hydrocarbon chain region of the bilayer. The last 8-ns fragment of the generated trajectory was used f...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/S0006-3495(01)75867-5
更新日期：2001-10-01 00:00:00
abstract：:The general formalism required to treat two-state sliding filament models of muscle contraction, including free energy considerations, is first reviewed and amplified. This formalism is then used to examine, and modify as needed, three models studied previously by Podolsky and Nolan, in which cross-bridge attachment-d...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/S0006-3495(75)85823-1
更新日期：1975-04-01 00:00:00
abstract：:This paper describes the use of electrospray ionization-Fourier transform ion cyclotron mass spectrometry (ESI-FTICR-MS) to study the relative stabilities of noncovalent complexes of carbonic anhydrase II (CAII, EC 4.2.1.1) and benzenesulfonamide inhibitors in the gas phase. Sustained off-resonance irradiation collisi...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/s0006-3495(99)77477-1
更新日期：1999-06-01 00:00:00
abstract：:The composition and electrolyte concentration of the aqueous bathing environment have important consequences for many biological processes and can profoundly affect the behavior of biomolecules. Nevertheless, because of computational limitations, many molecular simulations of biophysical systems can be performed only ...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/j.bpj.2018.02.042
更新日期：2018-05-22 00:00:00
abstract：:The interaction between actin and myosin in the filament array of glycerinated muscle fibers has been monitored using paramagnetic probes and mechanical measurements. Both fiber stiffness and the spectra of probes bound to a reactive sulfydral on the myosin head were measured as the actomyosin bond was weakened by add...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/S0006-3495(88)83136-9
更新日期：1988-04-01 00:00:00
abstract：:The centromeric histone H3 variant centromeric protein A (CENP-A), whose sequence is the least conserved among all histone variants, is responsible for specifying the location of the centromere. Here, we present a comprehensive study of CENP-A nucleosome arrays by cryo-electron tomography. We see that CENP-A arrays ha...
journal_title：Biophysical journal
pub_type： 杂志文章
doi：10.1016/j.bpj.2014.01.005
更新日期：2014-02-18 00:00:00
