|Entry||Database: PDB / ID: 6c1h|
|Title||High-Resolution Cryo-EM Structures of Actin-bound Myosin States Reveal the Mechanism of Myosin Force Sensing|
|Keywords||STRUCTURAL PROTEIN / Mechanochemistry / Mechanobiology / Structural Biology / Cytoskeleton / Molecular Motor / Myosin-I|
|Function / homology|
Function and homology information
actin filament-based movement / transferrin transport / vesicle transport along actin filament / CaM pathway / Sodium/Calcium exchangers / Cam-PDE 1 activation / Reduction of cytosolic Ca++ levels / microfilament motor activity / Calmodulin induced events / microfilament motor activity => GO:0000146 ...actin filament-based movement / transferrin transport / vesicle transport along actin filament / CaM pathway / Sodium/Calcium exchangers / Cam-PDE 1 activation / Reduction of cytosolic Ca++ levels / microfilament motor activity / Calmodulin induced events / microfilament motor activity => GO:0000146 / => GO:0120081 / Glycogen breakdown (glycogenolysis) / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / myosin complex / CLEC7A (Dectin-1) induces NFAT activation / Loss of phosphorylation of MECP2 at T308 / Activation of Ca-permeable Kainate Receptor / glycogen catabolic process / PKA activation / CREB1 phosphorylation through the activation of Adenylate Cyclase / mesenchyme migration / establishment of protein localization to mitochondrial membrane / organelle localization by membrane tethering / CaMK IV-mediated phosphorylation of CREB / regulation of cardiac muscle cell action potential / negative regulation of high voltage-gated calcium channel activity / N-terminal myristoylation domain binding / tropomyosin binding / autophagosome membrane docking / mitochondrion-endoplasmic reticulum membrane tethering / myosin heavy chain binding / Phase 0 - rapid depolarisation / Activation of RAC1 downstream of NMDARs / troponin I binding / type 3 metabotropic glutamate receptor binding / Ion transport by P-type ATPases / regulation of synaptic vesicle endocytosis / regulation of cell communication by electrical coupling involved in cardiac conduction / Negative regulation of NMDA receptor-mediated neuronal transmission / negative regulation of peptidyl-threonine phosphorylation / Unblocking of NMDA receptors, glutamate binding and activation / protein phosphatase activator activity / brush border / positive regulation of ryanodine-sensitive calcium-release channel activity / Synthesis of IP3 and IP4 in the cytosol / skeletal muscle thin filament assembly / actin filament bundle / striated muscle thin filament / filamentous actin / regulation of rhodopsin mediated signaling pathway / Smooth Muscle Contraction / response to corticosterone / catalytic complex / RHO GTPases activate PAKs / positive regulation of cyclic-nucleotide phosphodiesterase activity / Activation of AMPK downstream of NMDARs / adenylate cyclase binding / Long-term potentiation / inositol phosphate metabolic process / detection of calcium ion / phosphatidylinositol-3,4,5-trisphosphate binding / actin filament bundle assembly / actin monomer binding / Uptake and function of anthrax toxins / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / cytoskeletal motor activity / Protein methylation / skeletal muscle fiber development / negative regulation of ryanodine-sensitive calcium-release channel activity / regulation of cardiac muscle contraction / DARPP-32 events / skeletal muscle myofibril / adenylate cyclase activator activity / RHO GTPases activate IQGAPs / post-Golgi vesicle-mediated transport / calcium channel inhibitor activity / nitric-oxide synthase binding / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / positive regulation of phosphoprotein phosphatase activity / activation of adenylate cyclase activity / Inactivation, recovery and regulation of the phototransduction cascade / Ion homeostasis / stress fiber / trans-Golgi network membrane / voltage-gated potassium channel complex / regulation of heart rate / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Wnt signaling pathway, calcium modulating pathway / titin binding / tetrahydrobiopterin metabolic process / substantia nigra development / eNOS activation / sarcomere / actin filament polymerization / positive regulation of protein dephosphorylation / calcium channel complex / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / phosphatidylinositol 3-kinase binding / regulation of ryanodine-sensitive calcium-release channel activity
Similarity search - Function
Class I myosin tail homology domain / Unconventional myosin tail, actin- and lipid-binding / Class I myosin tail homology (TH1) domain profile. / Class I myosin, motor domain / Actin; Chain A, domain 2 / Actin; Chain A, domain 2 / IQ calmodulin-binding motif / Short calmodulin-binding motif containing conserved Ile and Gln residues. / Myosin head (motor domain) / Myosin head, motor domain ...Class I myosin tail homology domain / Unconventional myosin tail, actin- and lipid-binding / Class I myosin tail homology (TH1) domain profile. / Class I myosin, motor domain / Actin; Chain A, domain 2 / Actin; Chain A, domain 2 / IQ calmodulin-binding motif / Short calmodulin-binding motif containing conserved Ile and Gln residues. / Myosin head (motor domain) / Myosin head, motor domain / Myosin motor domain profile. / Myosin. Large ATPases. / IQ motif profile. / IQ motif, EF-hand binding site / ATPase, substrate binding domain, subdomain 4 / Actin; Chain A, domain 4 / Actins signature 1. / Actin, conserved site / Actins signature 2. / Actin/actin-like conserved site / Actins and actin-related proteins signature. / Actin / Actin family / Actin / Kinesin motor domain superfamily / ATPase, nucleotide binding domain / EF-hand domain pair / ATPase, nucleotide binding domain / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand calcium-binding domain. / EF-hand domain pair / Nucleotidyltransferase; domain 5 / Roll / Alpha-Beta Complex / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Actin, alpha skeletal muscle / ADENOSINE-5'-DIPHOSPHATE / Calmodulin-1 / Unconventional myosin-Ib
Similarity search - Component
|Biological species||Oryctolagus cuniculus (rabbit)|
Rattus norvegicus (Norway rat)
|Method||ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.9 Å|
|Authors||Mentes, A. / Huehn, A. / Liu, X. / Zwolak, A. / Dominguez, R. / Shuman, H. / Ostap, E.M. / Sindelar, C.V.|
|Funding support|| United States, 1items |
|Citation||Journal: Proc Natl Acad Sci U S A / Year: 2018|
Title: High-resolution cryo-EM structures of actin-bound myosin states reveal the mechanism of myosin force sensing.
Authors: Ahmet Mentes / Andrew Huehn / Xueqi Liu / Adam Zwolak / Roberto Dominguez / Henry Shuman / E Michael Ostap / Charles V Sindelar /
Abstract: Myosins adjust their power outputs in response to mechanical loads in an isoform-dependent manner, resulting in their ability to dynamically adapt to a range of motile challenges. Here, we reveal the ...Myosins adjust their power outputs in response to mechanical loads in an isoform-dependent manner, resulting in their ability to dynamically adapt to a range of motile challenges. Here, we reveal the structural basis for force-sensing based on near-atomic resolution structures of one rigor and two ADP-bound states of myosin-IB (myo1b) bound to actin, determined by cryo-electron microscopy. The two ADP-bound states are separated by a 25° rotation of the lever. The lever of the first ADP state is rotated toward the pointed end of the actin filament and forms a previously unidentified interface with the N-terminal subdomain, which constitutes the upper half of the nucleotide-binding cleft. This pointed-end orientation of the lever blocks ADP release by preventing the N-terminal subdomain from the pivoting required to open the nucleotide binding site, thus revealing how myo1b is inhibited by mechanical loads that restrain lever rotation. The lever of the second ADP state adopts a rigor-like orientation, stabilized by class-specific elements of myo1b. We identify a role for this conformation as an intermediate in the ADP release pathway. Moreover, comparison of our structures with other myosins reveals structural diversity in the actomyosin binding site, and we reveal the high-resolution structure of actin-bound phalloidin, a potent stabilizer of filamentous actin. These results provide a framework to understand the spectrum of force-sensing capacities among the myosin superfamily.
|Structure viewer||Molecule: |
Downloads & links
A: Actin, alpha skeletal muscle
B: Actin, alpha skeletal muscle
C: Actin, alpha skeletal muscle
D: Actin, alpha skeletal muscle
E: Actin, alpha skeletal muscle
P: Unconventional myosin-Ib
Mass: 41862.613 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P68135
Mass: 84143.930 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Rattus norvegicus (Norway rat) / References: UniProt: Q05096
Mass: 16721.350 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) unidentified (others) / References: UniProt: P0DP23*PLUS
Mass: 427.201 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: HELICAL ARRAY / 3D reconstruction method: helical reconstruction|
|Component||Name: Complex of actin, myosin-1b, and calmodulin with ADP / Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES|
|Molecular weight||Experimental value: NO|
|Source (natural)||Organism: unidentified (others)|
|Buffer solution||pH: 7|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Average exposure time: 11 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|Software||Name: PHENIX / Version: 1.11.1_2575: / Classification: refinement|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Helical symmerty||Angular rotation/subunit: -167.4 ° / Axial rise/subunit: 27.5 Å / Axial symmetry: C1|
|3D reconstruction||Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 62000 |
Details: Resolution estimated by post-processing in RELION using a mask with soft edges that included only the central subunit.
Symmetry type: HELICAL
|Atomic model building||Protocol: FLEXIBLE FIT / Space: REAL|
|Refine LS restraints|
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