Mechanistic study of the ATP hydrolysis reaction in dynein motor protein

2020 ◽  
Vol 22 (3) ◽  
pp. 1534-1542 ◽  
Author(s):  
Rabindra Nath Manna ◽  
Mandira Dutta ◽  
Biman Jana
Keyword(s):  
Atp Hydrolysis ◽  
Motor Protein ◽  
Hydrolysis Reaction ◽  
Mechanistic Study ◽  
Water Chain ◽  
Dynein Motor ◽  
Proton Relay

Our findings suggest the definitive requirement of a proton relay process mediated by a water-chain and the Glu1742 residue in the ATP hydrolysis reaction of a dynein motor.

scholarly journals Analysis of the Structural Mechanism of ATP Inhibition at the AAA1 Subunit of Cytoplasmic Dynein-1 Using a Chemical “Toolkit”

2021 ◽  
Vol 22 (14) ◽  
pp. 7704
Author(s):  
Sayi’Mone Tati ◽  
Laleh Alisaraie
Keyword(s):  
Binding Affinity ◽  
Atp Hydrolysis ◽  
Critical Role ◽  
Motor Protein ◽  
Structural Data ◽  
Retrograde Transport ◽  
Cytoplasmic Dynein ◽  
Motor Domain ◽  
Conformational Search ◽  
Structural Mechanism

Dynein is a ~1.2 MDa cytoskeletal motor protein that carries organelles via retrograde transport in eukaryotic cells. The motor protein belongs to the ATPase family of proteins associated with diverse cellular activities and plays a critical role in transporting cargoes to the minus end of the microtubules. The motor domain of dynein possesses a hexameric head, where ATP hydrolysis occurs. The presented work analyzes the structure–activity relationship (SAR) of dynapyrazole A and B, as well as ciliobrevin A and D, in their various protonated states and their 46 analogues for their binding in the AAA1 subunit, the leading ATP hydrolytic site of the motor domain. This study exploits in silico methods to look at the analogues’ effects on the functionally essential subsites of the motor domain of dynein 1, since no similar experimental structural data are available. Ciliobrevin and its analogues bind to the ATP motifs of the AAA1, namely, the walker-A (W-A) or P-loop, the walker-B (W-B), and the sensor I and II. Ciliobrevin A shows a better binding affinity than its D analogue. Although the double bond in ciliobrevin A and D was expected to decrease the ligand potency, they show a better affinity to the AAA1 binding site than dynapyrazole A and B, lacking the bond. In addition, protonation of the nitrogen atom in ciliobrevin A and D, as well as dynapyrazole A and B, at the N9 site of ciliobrevin and the N7 of the latter increased their binding affinity. Exploring ciliobrevin A geometrical configuration suggests the E isomer has a superior binding profile over the Z due to binding at the critical ATP motifs. Utilizing the refined structure of the motor domain obtained through protein conformational search in this study exhibits that Arg1852 of the yeast cytoplasmic dynein could involve in the “glutamate switch” mechanism in cytoplasmic dynein 1 in lieu of the conserved Asn in AAA+ protein family.

scholarly journals Meiosis-specific recombinase Dmc1 is a potent inhibitor of the Srs2 antirecombinase

2018 ◽  
Vol 115 (43) ◽  
pp. E10041-E10048 ◽  
Author(s):  
J. Brooks Crickard ◽  
Kyle Kaniecki ◽  
Youngho Kwon ◽  
Patrick Sung ◽  
Eric C. Greene
Keyword(s):  
Chromosome Segregation ◽  
Single Molecule ◽  
Atp Hydrolysis ◽  
Potent Inhibitor ◽  
Chromosomal Rearrangements ◽  
Motor Protein ◽  
Product Formation ◽  
Gross Chromosomal Rearrangements ◽  
Strand Annealing ◽  
Hydrolysis Activity

Cross-over recombination products are a hallmark of meiosis because they are necessary for accurate chromosome segregation and they also allow for increased genetic diversity during sexual reproduction. However, cross-overs can also cause gross chromosomal rearrangements and are therefore normally down-regulated during mitotic growth. The mechanisms that enhance cross-over product formation upon entry into meiosis remain poorly understood. In Saccharomyces cerevisiae, the Superfamily 1 (Sf1) helicase Srs2, which is an ATP hydrolysis-dependent motor protein that actively dismantles recombination intermediates, promotes synthesis-dependent strand annealing, the result of which is a reduction in cross-over recombination products. Here, we show that the meiosis-specific recombinase Dmc1 is a potent inhibitor of Srs2. Biochemical and single-molecule assays demonstrate that Dmc1 acts by inhibiting Srs2 ATP hydrolysis activity, which prevents the motor protein from undergoing ATP hydrolysis-dependent translocation on Dmc1-bound recombination intermediates. We propose a model in which Dmc1 helps contribute to cross-over formation during meiosis by antagonizing the antirecombinase activity of Srs2.

scholarly journals RecQ helicases in DNA repair and cancer targets

2020 ◽  
Vol 64 (5) ◽  
pp. 819-830
Author(s):  
Joseph A. Newman ◽  
Opher Gileadi
Keyword(s):  
Dna Repair ◽  
Small Molecules ◽  
Atp Hydrolysis ◽  
Cancer Therapeutics ◽  
Genome Integrity ◽  
Mechanistic Study ◽  
Synthetic Lethal ◽  
Recq Helicases ◽  
Repair Pathways ◽  
Higher Eukaryotes

Abstract Helicases are enzymes that use the energy derived from ATP hydrolysis to catalyze the unwinding of DNA or RNA. The RecQ family of helicases is conserved through evolution from prokaryotes to higher eukaryotes and plays important roles in various DNA repair pathways, contributing to the maintenance of genome integrity. Despite their roles as general tumor suppressors, there is now considerable interest in exploiting RecQ helicases as synthetic lethal targets for the development of new cancer therapeutics. In this review, we summarize the latest developments in the structural and mechanistic study of RecQ helicases and discuss their roles in various DNA repair pathways. Finally, we consider the potential to exploit RecQ helicases as therapeutic targets and review the recent progress towards the development of small molecules targeting RecQ helicases as cancer therapeutics.

Rab3D directs organelle transport by recruiting cytoplasmic dynein motor protein Tctex-1 to secretory membranes of osteoclast

Bone ◽  
2009 ◽  
Vol 44 ◽  
pp. S160 ◽  
Author(s):  
N.J. Pavlos ◽  
J. Xu ◽  
H. Feng ◽  
P. Ng ◽  
T. Cheng ◽  
...  
Keyword(s):  
Motor Protein ◽  
Cytoplasmic Dynein ◽  
Organelle Transport ◽  
Dynein Motor

scholarly journals 3P-164 Molecular mechanism of ATP hydrolysis reaction in F_1-ATPase molecular motor(The 46th Annual Meeting of the Biophysical Society of Japan)

2008 ◽  
Vol 48 (supplement) ◽  
pp. S152
Author(s):  
Abdul Rajjak Shaikh ◽  
Yuko Ito ◽  
Mitsunori Ikeguchi ◽  
Hiroshi Ueno ◽  
Hiroyuki Noji ◽  
...  
Keyword(s):  
Annual Meeting ◽  
Molecular Mechanism ◽  
Atp Hydrolysis ◽  
Molecular Motor ◽  
Hydrolysis Reaction ◽  
Biophysical Society

Unidirectional motion of microtubules and microspheres by Dynein motor protein

2007 ◽  
Author(s):  
Tetsutaro Murakami ◽  
Takeshi Sugie ◽  
Takahide Kon ◽  
Ryuji Yokokawa
Keyword(s):  
Motor Protein ◽  
Dynein Motor ◽  
Unidirectional Motion

scholarly journals The Neck Linker of Kinesin-1 Functions as a Regulator of ATP Hydrolysis Reaction

2012 ◽  
Vol 102 (3) ◽  
pp. 371a
Author(s):  
Xiao Ling ◽  
Masahide Kikkawa ◽  
Michio Tomishige
Keyword(s):  
Atp Hydrolysis ◽  
Hydrolysis Reaction

scholarly journals The mode of ATP-dependent microtubule-kinesin sliding in the auxotonic condition.

1995 ◽  
Vol 198 (8) ◽  
pp. 1809-1815
Author(s):  
I Shirakawa ◽  
K Oiwa ◽  
S Chaen ◽  
T Shimizu ◽  
H Tanaka ◽  
...  
Keyword(s):  
Atp Hydrolysis ◽  
Isometric Force ◽  
Motor Protein ◽  
Maximum Velocity ◽  
Assay System ◽  
Kinetic Properties ◽  
Elastic Coefficient ◽  
Vitro Assay ◽  
Coated Glass

Kinesin is a motor protein that converts chemical energy derived from ATP hydrolysis into mechanical work to transport cellular components along microtubules. We studied the properties of ATP-dependent microtubule-kinesin sliding with two different in vitro assay systems. In one assay system, a kinesin-coated glass microneedle (elastic coefficient, 1-2.5 pN microns -1) was made to slide along an axoneme. Using this system, we obtained the relationship between the force (= load) on the microneedle and the velocity of microneedle-kinesin sliding in the auxotonic condition, in which the load on the microtubule-kinesin contacts increased as sliding progressed. The force-velocity curve was upwardly convex (maximum velocity Vmax, 0.58 +/- 0.15 microns s-1; maximum isometric force P0, 5.0 +/- 1.6 pN) and was similar to that of in vitro actin-myosin sliding in the auxotonic condition, suggesting that the two motor protein systems have fundamental kinetic properties in common. In the other assay system, an axoneme attached to a glass microneedle (elastic coefficient, 4-5 pN microns -1) was made to slide on a kinesin-coated glass surface (Vmax, 0.68 +/- 0.17 microns s-1; P0, 46.1 +/- 18.6 pN). The change in shape of the axoneme indicated an enormous flexibility of randomly oriented kinesin molecules.

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