Microtubules play a central role in cytoskeletal changes during neuronal development and maintenance.Microtubule dynamics is essential to polarity and shape transitions underlying neural cell division,differentiation,...Microtubules play a central role in cytoskeletal changes during neuronal development and maintenance.Microtubule dynamics is essential to polarity and shape transitions underlying neural cell division,differentiation,motility,and maturation.Kinesin superfamily protein 2A is a member of human kinesin 13 gene family of proteins that depolymerize and destabilize microtubules.In dividing cells,kinesin superfamily protein 2A is involved in mitotic progression,spindle assembly,and chromosome segregation.In postmitotic neurons,it is required for axon/dendrite specification and extension,neuronal migration,connectivity,and survival.Humans with kinesin superfamily protein 2A mutations suffer from a variety of malformations of cortical development,epilepsy,autism spectrum disorder,and neurodegeneration.In this review,we discuss how kinesin superfamily protein 2A regulates neuronal development and function,and how its deregulation causes neurodevelopmental and neurological disorders.展开更多
Alzheimer’s disease（AD）is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles.Prior to the development of these characteristic pathological hallmarks of AD,ante...Alzheimer’s disease（AD）is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles.Prior to the development of these characteristic pathological hallmarks of AD,anterograde axonal transport is impaired.However,the key proteins that initiate these intracellular impairments remain elusive.The collapsin response mediator protein-2（CRMP-2）plays an integral role in kinesin-1-dependent axonal transport and there is evidence that phosphorylation of CRMP-2releases kinesin-1.Here,we tested the hypothesis that amyloid-beta（Aβ）-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1（an anterograde axonal motor transport protein）in AD.We found that brain sections and lysates from AD patients demonstrated elevated phosphorylation of CRMP-2 at the T555 site.Additionally,in the transgenic Tg2576 mouse model of familial AD（FAD）that exhibits Aβaccumulation in the brain with age,we found substantial co-localization of p T555CRMP-2and dystrophic neurites.In SH-SY5Y differentiated neuronal cultures,Aβ-dependent phosphorylation of CRMP-2 at the T555 site was also elevated and this reduced the CRMP-2 association with kinesin-1.The overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon elongation.These data suggest that Aβ-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport protein function,leading to neuronal defects.展开更多
Docking of the kinesin＇s neck linker （NL） to the motor domain is the key force-generation process of the kinesin. In this process, NL＇sβ10 portion forms four backbone hydrogen bonds （HBs） with the motor domain....Docking of the kinesin＇s neck linker （NL） to the motor domain is the key force-generation process of the kinesin. In this process, NL＇sβ10 portion forms four backbone hydrogen bonds （HBs） with the motor domain. These backbone hydrogen bonds show big differences in their effective strength. The origins of these strength differences are still unclear. Using molecular dynamics method, we investigate the stability of the backbone HBs in explicit water environment. We find that the strength differences of these backbone HBs mainly arise from their relationships with water molecules which are controlled by arranging the surrounding residue sidechains. The arrangement of the residues in the C-terminal part of /310 results in the existence of the water-attack channels around the backbone HBs in this region. Along these channels the water molecules can directly attack the backbone HBs and make these HBs relatively weak. In contrast, the backbone HB at the N-terminus ofβ 10 is protected by the surrounding hydrophobic and hydrophilic residues which cooperate positively with the central backbone HB and make this HB highly strong. The intimate relationship between the effective strength of protein backbone HB and water revealed here should be considered when performing mechanical analysis for protein conformational changes.展开更多
Grain shape is one of the important agronomic traits, which is closely related to the yield of rice.A new rice mutant, named small and round grain(srg1), was isolated from an indica cultivar Zhenong 34 by ethyl methan...Grain shape is one of the important agronomic traits, which is closely related to the yield of rice.A new rice mutant, named small and round grain(srg1), was isolated from an indica cultivar Zhenong 34 by ethyl methane sulfonate(EMS) mutagenesis. The microscopic analysis showed that the cell length of spikelet in srg1 was decreased compared with that in wild type(WT), which caused the grain length short.Meanwhile, the grains of srg1 were wider than those of WT because of the increased cell layers in spikelet in the lateral direction. Therefore, the inhibition of cell expansion and increased cell proliferation collectively led to the small and round grain. By map-based cloning, the gene SRG1 was located on the short arm of chromosome 9, which encodes a kinesin-4 protein, represented by the gene LOC_Os09 g02650. A single nucleotide polymorphism, occurred in the 16 th exon of SRG1, led to premature translation stop in mutant. The cell cycle-related genes were up-regulated in srg1, which conferred that SRG1 controlled grain width through the cell proliferation. Since the role of SRG1 in regulating grain shape was not clarified well before, it is valuable to explore the mechanism of grain development. This study could, hence, provide a morphogenesis and molecular basis for elucidating the function of SRG1, as well as a new germplasm resource for the further study of grain development.展开更多
Microtubules have been identified as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concern...Microtubules have been identified as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concerns that abnormally stabilizing microtubules may have only limited benefits for regeneration, while at the same time may be detrimental to the normal work that microtubules perform for the axon. Kinesin-5 （also called kifl I or EgS）, a molecular motor protein best known for its crucial role in mitosis, acts as a brake on microtubule movements by other motor proteins in the axon. Drugs that inhibit kinesin-5, originally developed to treat cancer, result in greater mobility of microtubules in the axon and an overall shift in the forces on the microtubule array. As a result, the axon grows faster, retracts less, and more readily enters environments that are inhibitory to axonal regeneration. Thus, drugs that inhibit kinesin-5 offer a novel microtubule-based means to boost axonal regeneration without the concerns that accompany abnormal stabilization of the microtubule array. Even so, inhibiting kinesin-5 is not without its own caveats, such as potential problems with navigation of the regenerating axon to its target, as well as morphological effects on dendrites that could affect learning and memory if the drugs reach the brain.展开更多
A fluctuating ratchet model of non-Markov process is presented to describe the processive movement of molecular motors of single-headed kinesin KIF1A, where the fluctuation perturbation to the local potential is intro...A fluctuating ratchet model of non-Markov process is presented to describe the processive movement of molecular motors of single-headed kinesin KIF1A, where the fluctuation perturbation to the local potential is introduced and the detailed ATPase pathway of the motor is included. The theoretical results show good quantitative agreement with the previous experimental ones.展开更多
Kinesin is a stepping molecular motor travelling along the microtubule. It moves primarily in the plus end direction of the microtubule and occasionally in the minus-end, backward, direction. Recently, the backward st...Kinesin is a stepping molecular motor travelling along the microtubule. It moves primarily in the plus end direction of the microtubule and occasionally in the minus-end, backward, direction. Recently, the backward steps of kinesin under different loads and temperatures start to attract interests, and the relations among them are revealed. This paper aims to theoretically understand these relations observed in experiments. After introducing a backward pathway into the previous model of the ATPase cycle of kinesin movement, the dependence of the backward movement on the load and the temperature is explored through Monte Carlo simulation. Our results agree well with previous experiments.展开更多
基金Fund for Scientific Research(FNRS)PDR T0236.20FNRS-Exellence of Science 30913351FNRS CDR J.0175.23(to FT)。
文摘Microtubules play a central role in cytoskeletal changes during neuronal development and maintenance.Microtubule dynamics is essential to polarity and shape transitions underlying neural cell division,differentiation,motility,and maturation.Kinesin superfamily protein 2A is a member of human kinesin 13 gene family of proteins that depolymerize and destabilize microtubules.In dividing cells,kinesin superfamily protein 2A is involved in mitotic progression,spindle assembly,and chromosome segregation.In postmitotic neurons,it is required for axon/dendrite specification and extension,neuronal migration,connectivity,and survival.Humans with kinesin superfamily protein 2A mutations suffer from a variety of malformations of cortical development,epilepsy,autism spectrum disorder,and neurodegeneration.In this review,we discuss how kinesin superfamily protein 2A regulates neuronal development and function,and how its deregulation causes neurodevelopmental and neurological disorders.
基金supported by King Abdul-Aziz University postgraduate scholarship(to SHM)the National Multiple Sclerosis Society(USA)Project Grant ID#RG43981/1(to SP)
文摘Alzheimer’s disease（AD）is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles.Prior to the development of these characteristic pathological hallmarks of AD,anterograde axonal transport is impaired.However,the key proteins that initiate these intracellular impairments remain elusive.The collapsin response mediator protein-2（CRMP-2）plays an integral role in kinesin-1-dependent axonal transport and there is evidence that phosphorylation of CRMP-2releases kinesin-1.Here,we tested the hypothesis that amyloid-beta（Aβ）-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1（an anterograde axonal motor transport protein）in AD.We found that brain sections and lysates from AD patients demonstrated elevated phosphorylation of CRMP-2 at the T555 site.Additionally,in the transgenic Tg2576 mouse model of familial AD（FAD）that exhibits Aβaccumulation in the brain with age,we found substantial co-localization of p T555CRMP-2and dystrophic neurites.In SH-SY5Y differentiated neuronal cultures,Aβ-dependent phosphorylation of CRMP-2 at the T555 site was also elevated and this reduced the CRMP-2 association with kinesin-1.The overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon elongation.These data suggest that Aβ-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport protein function,leading to neuronal defects.
基金Project supported by the National Natural Science Foundation of China(Grant No.11605038)the Open Project Program of State Key Laboratory of Theoretical Physics,Institute of Theoretical Physics,Chinese Academy of Sciences,China(Grant No.Y5KF211CJ1)
文摘Docking of the kinesin＇s neck linker （NL） to the motor domain is the key force-generation process of the kinesin. In this process, NL＇sβ10 portion forms four backbone hydrogen bonds （HBs） with the motor domain. These backbone hydrogen bonds show big differences in their effective strength. The origins of these strength differences are still unclear. Using molecular dynamics method, we investigate the stability of the backbone HBs in explicit water environment. We find that the strength differences of these backbone HBs mainly arise from their relationships with water molecules which are controlled by arranging the surrounding residue sidechains. The arrangement of the residues in the C-terminal part of /310 results in the existence of the water-attack channels around the backbone HBs in this region. Along these channels the water molecules can directly attack the backbone HBs and make these HBs relatively weak. In contrast, the backbone HB at the N-terminus ofβ 10 is protected by the surrounding hydrophobic and hydrophilic residues which cooperate positively with the central backbone HB and make this HB highly strong. The intimate relationship between the effective strength of protein backbone HB and water revealed here should be considered when performing mechanical analysis for protein conformational changes.
基金supported by the Science and Technology Office of Zhejiang Province(Grant Nos.2012C12901-2,2016C32085 and 2016C02050-6)
文摘Grain shape is one of the important agronomic traits, which is closely related to the yield of rice.A new rice mutant, named small and round grain(srg1), was isolated from an indica cultivar Zhenong 34 by ethyl methane sulfonate(EMS) mutagenesis. The microscopic analysis showed that the cell length of spikelet in srg1 was decreased compared with that in wild type(WT), which caused the grain length short.Meanwhile, the grains of srg1 were wider than those of WT because of the increased cell layers in spikelet in the lateral direction. Therefore, the inhibition of cell expansion and increased cell proliferation collectively led to the small and round grain. By map-based cloning, the gene SRG1 was located on the short arm of chromosome 9, which encodes a kinesin-4 protein, represented by the gene LOC_Os09 g02650. A single nucleotide polymorphism, occurred in the 16 th exon of SRG1, led to premature translation stop in mutant. The cell cycle-related genes were up-regulated in srg1, which conferred that SRG1 controlled grain width through the cell proliferation. Since the role of SRG1 in regulating grain shape was not clarified well before, it is valuable to explore the mechanism of grain development. This study could, hence, provide a morphogenesis and molecular basis for elucidating the function of SRG1, as well as a new germplasm resource for the further study of grain development.
基金discussed here on kinesin-5 inhibition as a means for augmenting nerve regeneration after injury was supported mainly by grants from the Craig H.Neilsen Foundation
文摘Microtubules have been identified as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concerns that abnormally stabilizing microtubules may have only limited benefits for regeneration, while at the same time may be detrimental to the normal work that microtubules perform for the axon. Kinesin-5 （also called kifl I or EgS）, a molecular motor protein best known for its crucial role in mitosis, acts as a brake on microtubule movements by other motor proteins in the axon. Drugs that inhibit kinesin-5, originally developed to treat cancer, result in greater mobility of microtubules in the axon and an overall shift in the forces on the microtubule array. As a result, the axon grows faster, retracts less, and more readily enters environments that are inhibitory to axonal regeneration. Thus, drugs that inhibit kinesin-5 offer a novel microtubule-based means to boost axonal regeneration without the concerns that accompany abnormal stabilization of the microtubule array. Even so, inhibiting kinesin-5 is not without its own caveats, such as potential problems with navigation of the regenerating axon to its target, as well as morphological effects on dendrites that could affect learning and memory if the drugs reach the brain.
基金Project supported by the National Natural Science Foundation of China （Nos. 60025516 and 10334100）.
文摘A fluctuating ratchet model of non-Markov process is presented to describe the processive movement of molecular motors of single-headed kinesin KIF1A, where the fluctuation perturbation to the local potential is introduced and the detailed ATPase pathway of the motor is included. The theoretical results show good quantitative agreement with the previous experimental ones.
基金Project supported by the National Natural Science Foundation of China (Grant Nos 10334100 and 10674173)
文摘Kinesin is a stepping molecular motor travelling along the microtubule. It moves primarily in the plus end direction of the microtubule and occasionally in the minus-end, backward, direction. Recently, the backward steps of kinesin under different loads and temperatures start to attract interests, and the relations among them are revealed. This paper aims to theoretically understand these relations observed in experiments. After introducing a backward pathway into the previous model of the ATPase cycle of kinesin movement, the dependence of the backward movement on the load and the temperature is explored through Monte Carlo simulation. Our results agree well with previous experiments.
