Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.4.4 (kinesin)
5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Islet-brain 1 [IB1; also termed c-Jun N-terminal kinase (JNK)-interacting protein 1 (JIP-1] is involved in the apoptotic signaling cascade of JNK and functions as a scaffold protein. It organizes several MAP kinases and the microtubule-transport motor protein kinesin and relates to other signal-transducing molecules such as the amyloid precursor protein. Here we have identified IB1/JIP-1 using different antibodies that reacted with either a monomeric or a dimeric form of IB1/JIP-1. By immunoelectron microscopy, differences in the subcellular localization were observed. The monomeric form was found in the cytoplasmic compartment and is associated with the cytoskeleton and with membranes, whereas the dimeric form was found in addition in nuclei. After treatment of mouse brain homogenates with alkaline phosphatase, the dimeric form disappeared and the monomeric form decreased its molecular weight, suggesting that an IB1/JIP-1 dimerization is phosphorylation dependent and that IB1 exists in several phospho- forms. N-methyl-D-aspartate receptor activation induced a dephosphorylation of IB1/JIP-1 in primary cultures of cortical neurons and reduced homodimerization. In conclusion, these data suggest that IB1/JIP-1 monomers and dimers may differ in compartmental localization and thus function as a scaffold protein of the JNK signaling cascade in the cytoplasm or as a transcription factor in nuclei.
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PMID:Phosphorylation-dependent dimerization and subcellular localization of islet-brain 1/c-Jun N-terminal kinase-interacting protein 1. 1766 63

Conventional kinesin is a dimeric motor protein that transports membranous organelles toward the plus-end of microtubules (MTs). Individual kinesin dimers show steadfast directionality and hundreds of consecutive steps, yet the detailed physical mechanism remains unclear. Here we compute free energies for the entire dimer-MT system for all possible interacting configurations by taking full account of molecular details. Employing merely first principles and several measured binding and barrier energies, the system-level analysis reveals insurmountable energy gaps between configurations, asymmetric ground state caused by mechanically lifted configurational degeneracy, and forbidden transitions ensuring coordination between both motor domains for alternating catalysis. This wealth of physical effects converts a kinesin dimer into a molecular ratchet-and-pawl device, which determinedly locks the dimer's movement into the MT plus-end and ensures consecutive steps in hand-over-hand gait. Under a certain range of extreme loads, however, the ratchet-and-pawl device becomes defective but not entirely abolished to allow consecutive back-steps. This study yielded quantitative evidence that kinesin's multiple molecular properties have been evolutionarily adapted to fine-tune the ratchet-and-pawl device so as to ensure the motor's distinguished performance.
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PMID:Kinesin is an evolutionarily fine-tuned molecular ratchet-and-pawl device of decisively locked direction. 1767 43

Fluorescence resonance energy transfer (FRET) is a spectroscopic phenomenon that consists of long-range dipole-dipole interaction between two chromophores. This method can be employed to gain quantitative distance information on macromolecules. FRET is particularly useful to characterize structural states of motor proteins, because the spatial relationship between various mechanical elements of the motor undergoing its mechanical cycle is essential to understand how force and movement are generated. In this chapter, we describe the technique, including the equations, methods of introducing fluorescence probes in specific loci of the protein, and data analysis. Practical guidelines and hints are also provided for protein preparation, labeling, and measuring FRET efficiency. The protocol is presented for interhead distance measurements in the dimeric kinesin-like motor, Ncd. However, it can easily be adapted to many other motor proteins.
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PMID:The use of FRET in the analysis of motor protein structure. 1795 19

Kinesin-1 (conventional kinesin) is a dimeric motor protein that carries cellular cargoes along microtubules by hydrolysing ATP and moving processively in 8-nm steps. The mechanism of processive motility involves the hand-over-hand motion of the two motor domains ('heads'), a process driven by a conformational change in the neck-linker domain of kinesin. However, the 'waiting conformation' of kinesin between steps remains controversial-some models propose that kinesin adopts a one-head-bound intermediate, whereas others suggest that both the kinesin heads are bound to adjacent tubulin subunits. Addressing this question has proved challenging, in part because of a lack of tools to measure structural states of the kinesin dimer as it moves along a microtubule. Here we develop two different single-molecule fluorescence resonance energy transfer (smFRET) sensors to detect whether kinesin is bound to its microtubule track by one or two heads. Our FRET results indicate that, while moving in the presence of saturating ATP, kinesin spends most of its time bound to the microtubule with both heads. However, when nucleotide binding becomes rate-limiting at low ATP concentrations, kinesin waits for ATP in a one-head-bound state and makes brief transitions to a two-head-bound intermediate as it walks along the microtubule. On the basis of these results, we suggest a model for how transitions in the ATPase cycle position the two kinesin heads and drive their hand-over-hand motion.
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PMID:How kinesin waits between steps. 1804 91

Neurospora crassa kinesin NcKin3 belongs to a unique fungal-specific subgroup of small Kinesin-3-related motor proteins. One of its functions appears to be the transport of mitochondria along microtubules. Here, we present the X-ray structure of a C-terminally truncated monomeric construct of NcKin3 comprising the motor domain and the neck linker, and a 3-D image reconstruction of this motor domain bound to microtubules, by cryoelectron microscopy. The protein contains Mg.ADP bound to the active site, yet the structure resembles an ATP-bound state. By comparison with structures of the Kinesin-3 motor Kif1A in different nucleotide states (Kikkawa, M. et al. (2001) Nature (London, U.K.) 411, 439-445), the NcKin3 structure corresponds to the AMPPCP complex of Kif1A rather than the AMPPNP complex. NcKin3-specific differences in the coordination of the nucleotide and asymmetric interactions between adjacent molecules in the crystal are discussed in the context of the unusual kinetics of the dimeric wild-type motor and the monomeric construct used for crystal structure analysis. The NcKin3 motor decorates microtubules at a stoichiometry of one head per alphabeta-tubulin heterodimer, thereby forming an axial periodicity of 8 nm. In spite of unusual extensions at the N-terminus and within flexible loops L2, L8a, and L12 (corresponding to the K-loop of monomeric kinesins), the microtubule binding geometry is similar to that of other members of the kinesin family.
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PMID:X-ray structure and microtubule interaction of the motor domain of Neurospora crassa NcKin3, a kinesin with unusual processivity. 1820 96

The stepping behavior of the dimeric kinesin is studied by using our model based on previous biochemical, X-ray crystallography and cryo-electron microscopy studies. It is shown that, when a Pi is released from the trailing head, a forward step is made under a backward load smaller than the stall force; while when a Pi is released from the leading head, no stepping is made under a forward load or no load, and a backward step is made under a backward load. The forward stepping time, i.e., the time from the release of Pi in the trailing head to the binding of the ADP head to next binding site, is much smaller than the dwell time even under the backward load near the stall force. Thus the movement velocity of the kinesin dimer can be considered to be only dependent on ATPase rates of the two heads. The duration of the rising phase, i.e., the actual time taken by the ADP head to transit from the trailing to leading positions, is on the time scale of microseconds under any backward load smaller than the stall force. This is consistent with available experimental results.
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PMID:Stepping behavior of two-headed kinesin motors. 1850 Nov 86

Many bio-molecular motors are dimers that move by a "hand-over-hand" mechanism along polar bio-polymeric tracks. Examples include kinesin, that "walks" on microtubule and myosin V that "walks" on actin. These molecular motors share two important symmetries. Typically the motor dimers have approximate mirror symmetry, and their tracks have translational, but not mirror, symmetry. Here we use a trajectory approach to analyze a minimal model for a generic dimeric motor that moves on a polymer track incorporating these two symmetry features. The analysis focuses of the relative probabilities of forward, reverse, backward, backward reverse trajectories and provides an experimentally accessible measure of the relative importance of a "Brownian motor" vs. "Power stroke" mechanism. Reciprocal relations, similar to those derived for the linear regime by Onsager for the fluxes (generalized velocities), hold for arbitrary magnitude forces (i.e., far from the linear regime) for the net probabilities for stepping and for chemical reaction.
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PMID:Symmetry based mechanism for hand-over-hand molecular motors. 1858 24

Kinesin-1 is a dimeric motor protein that transports cellular cargo along microtubules by using the energy released from ATP hydrolysis and moving processively in 8-nm steps. Recent novel studies at the single molecular level have provided extensive knowledge on how kinesin-1 converts the free energy of ATP hydrolysis and uses it for "walking" along microtubules. In this review, I have discussed the important topics pertaining to the energetics of kinesin-1 stepping mechanism and the consensus walking model.
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PMID:Energetics of kinesin-1 stepping mechanism. 1894 5

Using dipolar continuous-wave and pulsed electron paramagnetic resonance methods, we have determined the distribution of the distances between two spin labels placed on the middle of each of the neck linkers of dimeric kinesin. In the absence of microtubules, the distance was centered at 3.3 nm, but displayed a broad distribution with a width of 2.7 nm. This broad distribution implies that the linkers are random coils and extend well beyond the 2.5-nm distance expected of crystal structures. In the presence of microtubules, two linker populations were found: one similar to that observed in the absence of microtubules (a broad distribution centered at 3.3 nm), and the second population with a narrower distribution centered at 1.3-2.5 nm. In the absence of nucleotide but in the presence of microtubules, approximately 40% of the linkers were at a distance centered at 1.9 nm with a 1.2-nm width; the remaining fraction was at 3.3 nm, as before. This suggests that neck linkers exhibit dynamics covering a wide distance range between 1.0 and 5.0 nm. In the presence of ATP analogs adenosine 5'-(beta,gamma-imido)triphosphate and adenosine 5'-(gamma-thio)triphosphate, 40-50% of the spins showed a very narrow distribution centered at 1.6 nm, with a width of 0.4-0.5 nm. The remaining population displayed the broad 3.3-nm distribution. Under these conditions, a large fraction of linkers are docked firmly onto a motor core or microtubule, while the remainder is disordered. We propose that large nucleotide-dependent flexibility changes in the linkers contribute to the directional bias of the kinesin molecule stepping 8 nm along the microtubule.
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PMID:Nucleotide-induced flexibility change in neck linkers of dimeric kinesin as detected by distance Measurements using spin-labeling EPR. 1915 43

Molecular motors drive key biological processes such as cell division, intracellular organelle transport, and sperm propulsion and defects in motor function can give rise to various human diseases. Two dimeric microtubule-based motor proteins, kinesin-1 and cytoplasmic dynein can take over one hundred steps without detaching from the track. In this review, we discuss how these processive motors coordinate the activities of their two identical motor domains so that they can walk along microtubules.
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PMID:Walking the walk: how kinesin and dynein coordinate their steps. 1917 63


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