keyword
MENU ▼
Read by QxMD icon Read
search

autoinhibition

keyword
https://www.readbyqxmd.com/read/28638935/jip1-and-jip3-cooperate-to-mediate-trkb-anterograde-axonal-transport-by-activating-kinesin-1
#1
Tao Sun, Yuan Li, Ting Li, Huixian Ma, Yunyun Guo, Xingyu Jiang, Ming Hou, Shuhong Huang, Zheyu Chen
Long-range anterograde axonal transport of TrkB is important for neurons to exert appropriate BDNF responses. TrkB anterograde axonal delivery is mediated by kinesin-1, which associates with TrkB via the adaptor protein JIP3 or the Slp1/Rab27B/CRMP-2 protein complex. However, little is known about the activation mechanisms of TrkB-loaded kinesin-1. Here, we show that JIP1 mediates TrkB anterograde axonal transport using JIP1 knockout mice, sciatic nerve ligation analysis and live imaging. Next, we proved that JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport...
June 21, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28620171/mechanical-stability-of-talin-rod-controls-cell-migration-and-substrate-sensing
#2
Rolle Rahikainen, Magdaléna von Essen, Markus Schaefer, Lei Qi, Latifeh Azizi, Conor Kelly, Teemu O Ihalainen, Bernhard Wehrle-Haller, Martin Bastmeyer, Cai Huang, Vesa P Hytönen
Cells adhere to the surrounding tissue and probe its mechanical properties by forming cell-matrix adhesions. Talin is a critical adhesion protein and participates in the transmission of mechanical signals between extracellular matrix and cell cytoskeleton. Force induced unfolding of talin rod subdomains has been proposed to act as a cellular mechanosensor, but so far evidence linking their mechanical stability and cellular response has been lacking. Here, by utilizing computationally designed mutations, we demonstrate that stepwise destabilization of the talin rod R3 subdomain decreases cellular traction force generation, which affects talin and vinculin dynamics in cell-matrix adhesions and results in the formation of talin-rich but unstable adhesions...
June 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28607149/polycomb-repressive-complex-2-in-an-autoinhibited-state
#3
Matthew Bratkowski, Xin Yang, Xin Liu
Polycomb-group proteins control many fundamental biological processes, such as anatomical development in mammals and vernalization in plants. Polycomb repressive complex 2 (PRC2) is responsible for methylation of histone H3 lysine 27 (H3K27), and trimethylated H3K27 (H3K27me3) is implicated in epigenetic gene silencing. Recent genomic, biochemical, and structural data indicate that PRC2 is broadly conserved from yeast to human in many aspects. Here, we determined the crystal structure of an apo PRC2 from the fungus Chaetomium thermophilum captured in a bona fide autoinhibited state, which represents a novel conformation of PRC2 associated with enzyme regulation in light of the basal and stimulated states that we reported previously...
June 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28576829/differential-effects-of-the-dynein-regulatory-factor-lissencephaly-1-on-processive-dynein-dynactin-motility
#4
Pedro A Gutierrez, Bryce E Ackermann, Michael Vershinin, Richard J McKenney
Cytoplasmic dynein is the primary minus-end directed microtubule motor protein in animal cells, performing a wide range of motile activities, including transport of vesicular cargos, mRNAs, viruses, and proteins. Lissencephaly-1 (LIS1) is a highly conserved dynein-regulatory factor that binds directly to the dynein motor domain, uncoupling the enzymatic and mechanical cycles of the motor and stalling dynein on the microtubule track. Dynactin, another ubiquitous dynein-regulatory factor, releases dynein from an autoinhibited state, leading to a dramatic increase in fast, processive dynein motility...
June 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28548966/targeting-shp-1-stat3-signaling-a-promising-therapeutic-approach-for-the-treatment-of-cholangiocarcinoma
#5
Ming-Hung Hu, Li-Ju Chen, Yen-Lin Chen, Ming-Shen Tsai, Chung-Wai Shiau, Tzu-I Chao, Chun-Yu Liu, Jia-Horng Kao, Kuen-Feng Chen
Sorafenib is a multiple kinase inhibitor which targets Raf kinases, VEGFR, and PDGFR and is approved for the treatment of hepatocellular carcinoma (HCC). Previously, we found that p-STAT3 is a major target of SC-43, a sorafenib derivative. In this study, we report that SC-43-induced apoptosis in cholangiocarcinoma (CCA) via a novel mechanism. Three CCA cell lines (HuCCT-1, KKU-100 and CGCCA) were treated with SC-43 to determine their sensitivity to SC-43-induced cell death and apoptosis. We found that SC-43 activated SH2 domain-containing phosphatase 1 (SHP-1) activity, leading to p-STAT3 and downstream cyclin B1 and Cdc2 downregulation, which induced G2-M arrest and apoptotic cell death...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28541184/the-step-wise-pathway-of-septin-hetero-octamer-assembly-in-budding-yeast
#6
Andrew Weems, Michael McMurray
Septin proteins bind guanine nucleotides and form rod-shaped hetero-oligomers. Cells choose from a variety of available septins to assemble distinct hetero-oligomers, but the underlying mechanism was unknown. Using a new in vivo assay, we find that a stepwise assembly pathway produces the two species of budding yeast septin hetero-octamers: Cdc11/Shs1-Cdc12-Cdc3-Cdc10-Cdc10-Cdc3-Cdc12-Cdc11/Shs1. Rapid GTP hydrolysis by monomeric Cdc10 drives assembly of the core Cdc10 homodimer. The extended Cdc3 N terminus autoinhibits Cdc3 association with Cdc10 homodimers until prior Cdc3-Cdc12 interaction...
May 25, 2017: ELife
https://www.readbyqxmd.com/read/28537552/structure-analyses-reveal-a-regulated-oligomerization-mechanism-of-the-plexind1-gipc-myosin-vi-complex
#7
Guijun Shang, Chad A Brautigam, Rui Chen, Defen Lu, Jesús Torres-Vázquez, Xuewu Zhang
The GIPC family adaptor proteins mediate endocytosis by tethering cargo proteins to the myosin VI motor. The structural mechanisms for the GIPC/cargo and GIPC/myosin VI interactions remained unclear. PlexinD1, a transmembrane receptor that regulates neuronal and cardiovascular development, is a cargo of GIPCs. GIPC-mediated endocytic trafficking regulates PlexinD1 signaling. Here, we unravel the mechanisms of the interactions among PlexinD1, GIPCs and myosin VI by a series of crystal structures of these proteins in apo or bound states...
May 24, 2017: ELife
https://www.readbyqxmd.com/read/28522792/transgenic-autoinhibition-of-p21-activated-kinase-exacerbates-synaptic-impairments-and-fronto-dependent-behavioral-deficits-in-an-animal-model-of-alzheimer-s-disease
#8
Cyril Bories, Dany Arsenault, Myriam Lemire, Cyntia Tremblay, Yves De Koninck, Frédéric Calon
Defects in p21-activated kinase (PAK) lead to dendritic spine abnormalities and are sufficient to cause cognition impairment. The decrease in PAK in the brain of Alzheimer's disease (AD) patients is suspected to underlie synaptic and dendritic disturbances associated with its clinical expression, particularly with symptoms related to frontal cortex dysfunction. To investigate the role of PAK combined with Aβ and tau pathologies (3xTg-AD mice) in the frontal cortex, we generated a transgenic model of AD with a deficit in PAK activity (3xTg-AD-dnPAK mice)...
May 16, 2017: Aging
https://www.readbyqxmd.com/read/28500026/the-hect-e3-ubiquitin-ligase-wwp2-is-autoinhibited-by-a-peptide-linker
#9
(no author information available yet)
Peptide linkers that tether WWP2 WW domains lock the HECT domain in an inactive conformation.
May 12, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28486782/role-of-n-glycosylation-in-egfr-ectodomain-ligand-binding
#10
Maryam Azimzadeh Irani, Srinivasaraghavan Kannan, Chandra Verma
The epidermal growth factor receptor (EGFR) is a tyrosine kinase protein, overexpressed in several cancers. The extracellular domain of EGFR is known to be heavily glycosylated. Growth factor (mostly epidermal growth factor or EGF) binding activates EGFR. This occurs by inducing the transition from the autoinhibited tethered conformation to an extended conformation of the monomeric form of EGFR and by stabilizing the flexible preformed dimer. Activated EGFR adopts a back-to-back dimeric conformation after binding of another homologous receptor to its extracellular domain as the dimeric partner...
May 9, 2017: Proteins
https://www.readbyqxmd.com/read/28477408/autoinhibition-of-munc18-1-modulates-synaptobrevin-binding-and-helps-to-enable-munc13-dependent-regulation-of-membrane-fusion
#11
Ewa Sitarska, Junjie Xu, Seungmee Park, Xiaoxia Liu, Bradley Quade, Karolina Stepien, Kyoko Sugita, Chad A Brautigam, Shuzo Sugita, Josep Rizo
Munc18-1 orchestrates SNARE complex assembly together with Munc13-1 to mediate neurotransmitter release. Munc18-1 binds to synaptobrevin, but the relevance of this interaction and its relation to Munc13 function are unclear. NMR experiments now show that Munc18-1 binds specifically and non-specifically to synaptobrevin. Specific binding is inhibited by a L348R mutation in Munc18-1 and enhanced by a D326K mutation designed to disrupt the 'furled conformation' of a Munc18-1 loop. Correspondingly, the activity of Munc18-1 in reconstitution assays that require Munc18-1 and Munc13-1 for membrane fusion is stimulated by the D326K mutation and inhibited by the L348R mutation...
May 6, 2017: ELife
https://www.readbyqxmd.com/read/28475870/a-tunable-brake-for-hect-ubiquitin-ligases
#12
Zan Chen, Hanjie Jiang, Wei Xu, Xiaoguang Li, Daniel R Dempsey, Xiangbin Zhang, Peter Devreotes, Cynthia Wolberger, L Mario Amzel, Sandra B Gabelli, Philip A Cole
The HECT E3 ligases ubiquitinate numerous transcription factors and signaling molecules, and their activity must be tightly controlled to prevent cancer, immune disorders, and other diseases. In this study, we have found unexpectedly that peptide linkers tethering WW domains in several HECT family members are key regulatory elements of their catalytic activities. Biochemical, structural, and cellular analyses have revealed that the linkers can lock the HECT domain in an inactive conformation and block the proposed allosteric ubiquitin binding site...
May 4, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28459430/chemotherapy-drugs-induce-pyroptosis-through-caspase-3-cleavage-of-a-gasdermin
#13
Yupeng Wang, Wenqing Gao, Xuyan Shi, Jingjin Ding, Wang Liu, Huabin He, Kun Wang, Feng Shao
Pyroptosis, activated by the canonical caspase-1 inflammasomes or caspase-4/5/11 by cytosolic LPS, is critical for immunity(1,2,3). The caspases cleave Gasdermin D (GSDMD) in the middle linker to release autoinhibition on its Gasdermin-N domain that executes pyroptosis via the pore-forming activity(4,5,6,7,8,9). GSDMD belongs to a Gasdermin family sharing the pore-forming domain(4,6,10). The function and mechanism of activation for other Gasdermins are unknown. Here we show that GSDME, originally identified as DFNA5 (Deafness, Autosomal Dominant 5)(11), could switch TNFα or chemotherapy drugs-induced and caspase-3-mediated apoptosis to pyroptosis...
May 1, 2017: Nature
https://www.readbyqxmd.com/read/28452363/mechanism-of-sos-pr-domain-autoinhibition-revealed-by-single-molecule-assays-on-native-protein-from-lysate
#14
Young Kwang Lee, Shalini T Low-Nam, Jean K Chung, Scott D Hansen, Hiu Yue Monatrice Lam, Steven Alvarez, Jay T Groves
The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) plays a critical role in signal transduction by activating Ras. Here we introduce a single-molecule assay in which individual SOS molecules are captured from raw cell lysate using Ras-functionalized supported membrane microarrays. This enables characterization of the full-length SOS protein, which has not previously been studied in reconstitution due to difficulties in purification. Our measurements on the full-length protein reveal a distinct role of the C-terminal proline-rich (PR) domain to obstruct the engagement of allosteric Ras independently of the well-known N-terminal domain autoinhibition...
April 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28438902/crucial-role-of-rock2-mediated-phosphorylation-and-upregulation-of-fhod3-in-the-pathogenesis-of-angiotensin-ii-induced-cardiac-hypertrophy
#15
Qing Zhou, Si-Si Wei, Hong Wang, Qian Wang, Wei Li, Gang Li, Jian-Wen Hou, Xiao-Meng Chen, Jie Chen, Wei-Ping Xu, Yi-Gang Li, Yue-Peng Wang
Cardiac hypertrophy is characterized by increased myofibrillogenesis. Angiotensin II (Ang-II) is an essential mediator of the pressure overload-induced cardiac hypertrophy in part through RhoA/ROCK (small GTPase/Rho-associated coiled-coil containing protein kinase) pathway. FHOD3 (formin homology 2 domain containing 3), a cardiac-restricted member of diaphanous-related formins, is crucial in regulating myofibrillogenesis in cardiomyocytes. FHOD3 maintains inactive through autoinhibition by an intramolecular interaction between its C- and N-terminal domains...
June 2017: Hypertension
https://www.readbyqxmd.com/read/28427457/integrative-modelling-of-tir-domain-containing-adaptor-molecule-inducing-interferon-%C3%AE-trif-provides-insights-into-its-autoinhibited-state
#16
Jarjapu Mahita, Ramanathan Sowdhamini
BACKGROUND: TRIF is a key protein in antiviral innate immunity, operating downstream of TLRs. TRIF activation leads to the production of interferon-β and pro-inflammatory cytokines. There is evidence from experiments to suggest that the N-terminal domain of TRIF binds to its TIR domain to avoid constitutive activation. However, no structure of a complex between the N-terminal domain and the TIR domain exists till date. The disordered nature of the region connecting the N-terminal domain and the TIR domain compounds the issue of elucidating the mechanism of autoinhibition of TRIF...
April 20, 2017: Biology Direct
https://www.readbyqxmd.com/read/28426203/tyrosine-kinase-activation-and-conformational-flexibility-lessons-from-src-family-tyrosine-kinases
#17
Yilin Meng, Matthew P Pond, Benoît Roux
Protein kinases are enzymes that catalyze the covalent transfer of the γ-phosphate of an adenosine triphosphate (ATP) molecule onto a tyrosine, serine, threonine, or histidine residue in the substrate and thus send a chemical signal to networks of downstream proteins. They are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Unregulated protein kinase activity is often associated with a wide range of diseases, therefore making protein kinases major therapeutic targets...
April 20, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28425706/allosteric-autoinhibition-pathway-in-transcription-factor-erg-dynamics-network-and-mutant-experimental-evaluations
#18
Wei Ye, Tianle Qian, Hao Liu, Ray Luo, Hai-Feng Chen
Allosteric autoinhibition exists in many transcription factors. The ERG proteins exhibit autoinhibition on DNA binding by the C-terminal and N-terminal inhibitory domains (CID and NID). However, the autoinhibition mechanism and allosteric pathway of ERG are unknown. In this study we intend to elucidate the residue-level allosteric mechanism and pathway via a combined approach of computational and experimental analyses. Specifically computational residue-level fluctuation correlation data was analyzed to reveal detailed dynamics signatures in the allosteric autoinhibition process...
April 25, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28420739/the-dnak-chaperone-uses-different-mechanisms-to-promote-and-inhibit-replication-of-vibrio-cholerae-chromosome-2
#19
Jyoti K Jha, Mi Li, Rodolfo Ghirlando, Lisa M Miller Jenkins, Alexander Wlodawer, Dhruba Chattoraj
Replication of Vibrio cholerae chromosome 2 (Chr2) depends on molecular chaperone DnaK to facilitate binding of the initiator (RctB) to the replication origin. The binding occurs at two kinds of site, 12-mers and 39-mers, which promote and inhibit replication, respectively. Here we show that DnaK employs different mechanisms to enhance the two kinds of binding. We found that mutations in rctB that reduce DnaK binding also reduce 12-mer binding and initiation. The initiation defect is suppressed by second-site mutations that increase 12-mer binding only marginally...
April 18, 2017: MBio
https://www.readbyqxmd.com/read/28414322/parkin-phosphoubiquitin-complex-reveals-cryptic-ubiquitin-binding-site-required-for-rbr-ligase-activity
#20
Atul Kumar, Viduth K Chaugule, Tara E C Condos, Kathryn R Barber, Clare Johnson, Rachel Toth, Ramasubramanian Sundaramoorthy, Axel Knebel, Gary S Shaw, Helen Walden
RING-between-RING (RBR) E3 ligases are a class of ubiquitin ligases distinct from RING or HECT E3 ligases. An important RBR ligase is Parkin, mutations in which lead to early-onset hereditary Parkinsonism. Parkin and other RBR ligases share a catalytic RBR module but are usually autoinhibited and activated via distinct mechanisms. Recent insights into Parkin regulation predict large, unknown conformational changes during Parkin activation. However, current data on active RBR ligases reflect the absence of regulatory domains...
May 2017: Nature Structural & Molecular Biology
keyword
keyword
98505
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"