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Introduction: Background Material
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
In most cells, substances move within the cell by diffusion. In the case of neurons having long axons, however, some other mechanism must be used to exchange substances between the cell body and the distal parts of axons. Specialized motor proteins, fueled by ATP, move substances in the retrograde (toward the cell body) and orthograde (away from the cell body), directions using microtubules as “tracks”. Some substances, such as cytoskeletal proteins, are transported at a slow rate of 1–10 mm/day, whereas other substances, such as enzymes, lipids, and other small-molecular weight material, are transported at a fast rate of up to 400 mm/day. Mitochondria are transported at an intermediate rate. Axonal transport is discussed further in Section 5.2 in connection with the neuromuscular junction.
Manipulating the Intracellular Trafficking of Nucleic Acids
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Kathleen E. B Meyer, Lisa S. Uyechi, Francis C. Szoka
The motor proteins are believed to attach to receptor proteins anchored in organelle membranes, and two such receptor proteins have been identified and are currently under investigation (73). The kinectin protein is thought to join kinesin to the organelle membrane. Kinectin is predicted by its amino acid sequence to form a coiled-coil motif and is anchored in the membrane by its N-terminal sequence (74). Antibodies to kinectin, blocking potential binding sites for kinesin, inhibit plus-end-directed organelle movement in vitro by 90% (75). The dynactin complex, consisting of 10 different polypeptides, is capable of interacting with cytoplasmin dynein as well as microtubules, kinetochores, and membranes (73), yet the molecular events involved in attachment have not been elucidated. The interaction of microtubules with membranous organelles also appears to involve linker protein, or CLIPS, that bind to membranes via protein receptors (73,76). It remains to be determined whether additional kinectin- or dynactinlike proteins exist, which receptor proteins are found on specific organelles, and how organelle movement is orchestrated.
Pharmacologic Ascorbate Influences Multiple Cellular Pathways Preferentially in Cancer Cells
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Qi Chen, Kishore Polireddy, Ping Chen, Ramesh Balusu, Tao Wang, Ruochen Dong
Microtubules act as tracks for cargo transport with the help of motor proteins (kinesin and dynein) in and out of the cells. The motor proteins kinesin and dynein associate with cargoes and transport them along microtubules. Tubulin posttranslational modifications are associated with the recruitment of specific types of motor molecules. For example, acetylated α-tubulin specifically interacts with kinesin 1 cargo complex, whereas tyrosinated α-tubulin interacts with kinesin 3 cargo complex [65]. Assuming from the fact that pharmacologic ascorbate enhanced α-tubulin acetylation, it is possible that cargo transport is influenced. Currently, there efforts have not been made to understand the effect of ascorbate on cargo transport mediated by motor proteins. This question is particularly important in neuronal transport, that ascorbate might have pathophysiologic or therapeutic implication for diseases of the nervous system. Microtubules in the axon organize into bundles and enable efficient transport of neurotransmitters. Such bundled microtubules are also observed in primary cilia and flagella, as well as in mitotic spindles. Often, these microtubules are marked by acetylation. Further research is required to address these intriguing questions.
Syntaphilin mediates axonal growth and synaptic changes through regulation of mitochondrial transport: a potential pharmacological target for neurodegenerative diseases
Published in Journal of Drug Targeting, 2023
Qing-Yun Wu, Hui-Lin Liu, Hai-Yan Wang, Kai-Bin Hu, Ping Liao, Sen Li, Zai-Yun Long, Xiu-Min Lu, Yong-Tang Wang
Two types of motor proteins, the kinesins family and the dyneins family, bind to microtubules. The kinesin superfamily has 14 families, of which Kinesin-1 family members (KIF5) are the main motors driving neuronal mitochondrial forward transport along microtubules [26]. Kinesin-1 is usually a heterotetramer composed of two light chains (KLC) and two heavy chains (KHC). KLC contributes to the association of Kinesin-1 with mitochondria and the regulation of activity, while KHC provides power by hydrolysing ATP and carries out axonal transport along the microtubule. Targeted disruption of KIF5 expression in mice inhibits mitochondrial motor function and leads to mitochondrial accumulation in the perinuclear region. Although mutations of the KHC gene in Drosophila melanogaster severely reduced mitochondrial transport in neurons, they were not completely eliminated, suggesting that other protein motors are involved in driving mitochondrial transport. In addition to KIF5, some members of the Kinesin-3 family are also involved in axonal mitochondrial transport [27]. However, the exact mechanism of their role in mitochondrial transport requires further investigation.
Discovery of a novel Aurora B inhibitor GSK650394 with potent anticancer and anti-aspergillus fumigatus dual efficacies in vitro
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Yuhua He, Wei Fu, Liyang Du, Huiqiao Yao, Zhengkang Hua, Jinyu Li, Zhonghui Lin
It is well known that ATP is the primary carrier of energy in cells. Upon hydrolysis, it releases energy from the chemical bonds to fuel cellular processes. For example, ATP hydrolysis by motor proteins or DNA helicases can induce conformational changes and thus drive the translocation of these proteins. In addition, the protein kinases regulate various biological processes by transferring a phosphate group from ATP to amino acid residues like serine, threonine, or tyrosine. Interestingly, the mitotic kinases Aurora B, Haspin, and Bub132 also possess intrinsic ATPase activity, producing free inorganic phosphate. It is currently unknown whether this energy-consuming activity has a physiological role in cells, further studies are needed to address this potentially interesting question.
The association between serum sex hormone-binding globulin changes during progestin-primed ovarian stimulation and embryo outcomes: a retrospective cohort study
Published in Gynecological Endocrinology, 2022
Kai Deng, Kui Fu, Yueyue Hu, Ying Zhang, Changjun Zhang
SHBG is produced and secreted primarily by the liver, and it is positively correlated with the metabolic level [18]. Many studies have suggested that SHBG is closely related to metabolic activity. Patients with insulin resistance (IR), type 2 diabetes mellitus (T2D), fatty liver and other metabolic diseases have lower SHBG levels than normal people [19–21]. Oocyte meiosis utilizes a large amount of energy. The normal function of motor proteins and centromere-related kinases requires a high ATP supply, and their abnormal functions lead to abnormal spindle assembly, chromosome arrangement and, eventually, aneuploid oocytes [22]. The mitochondria of human embryos are all from oocytes, and the mitochondrial genetic pattern of embryos at stages 2–4 cells is disproportionate. The cleavage of embryos lacking mitochondria tends to cause cell lysis and death, and sufficient energy is key to the development of embryos [23]. Energy metabolism is crucial for oocyte maturation, fertilization and embryonic development [24]. Therefore, the increase in SHBG at the late follicular phase and on the HCG day is related to the more active cell metabolic state, which may be an important reason for the positive correlation between SHBG and oocyte/embryo quality. Hence, we reason that the SHBG elevation in the late follicular phase and on the HCG day provides adequate energy and optimizes the metabolism of fatty acids and glucose in follicles for appropriate ovarian function regulated by HNF-4α. HNF-4α upregulates downstream target gene expression of SHBG, TTR and PPL, improving the developmental competence of oocytes.