Classification and Application Progress of Molecular Motors in the Field of Medicine
LI Yuan1, LIU Nan2, LI Shuang-shuang1, ZHANG Hui2, LI Ming-yuan1*, ZHENG Ai-ping2*
1. Tianjin Enterprise Key Laboratory for Application Research of Hyaluronic Acid, College of Biotechnology, Tianjin University of Science &Technology, Tianjin 300457, China; 2. Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China
Abstract：As an important part of organism, molecular motor is a kind of protein nanomachine, which is involved in intracellular material transport, mitosis and construction of cytoskeleton. There are many types of molecular motors, for example, dynein and kinesin that achieve directional motion along microtubules, myosin that orbits around actin filaments, ATP synthase, and flagellum motors that use transmembrane transport to power them. The impediment of intracellular molecular motor transport would cause many diseases, such as stomach cancer, Alzheimer′s disease and melanoma. The directional motion of molecular motor makes it possible to target diseases, so the research on molecular motor is of great significance and has become one of the research hotspots in the field of medicine. In this review, the types, structure, main functions and motion mechanism of molecular motors are firstly introduced in detail. Then, the application progress of molecular motors in recent years is summarized. Finally, the future prospect and current problems are described in this paper.
李媛, 刘楠, 李双双, 张慧, 李明媛, 郑爱萍. 分子马达的分类及其在医药领域的应用进展[J]. 中国药学杂志, 2020, 55(22): 1829-1835.
LI Yuan, LIU Nan, LI Shuang-shuang, ZHANG Hui, LI Ming-yuan, ZHENG Ai-ping. Classification and Application Progress of Molecular Motors in the Field of Medicine. Chinese Pharmaceutical Journal, 2020, 55(22): 1829-1835.
LIN L F, WANG H Q, MA H. Directed transport properties of double-headed molecular motors with balanced cargo [J]. Physica A, 2019, 517: 270-279.
[2]
DELROSSO N V, DERR N D. Exploiting molecular motors as nanomachines: the mechanisms of de novo and re-engineered cytoskeletal motors [J]. Curr Opin Biotechnol, 2017, 46: 20-26.
[3]
GOYCHUK I. Perfect anomalous transport of subdiffusive cargos by molecular motors in viscoelastic cytosol [J]. Biosystems, 2019, 177: 56-65.
[4]
XIE P, GUO S K, CHEN H. A generalized kinetic model for coupling between stepping and ATP hydrolysis of kinesin molecular motors[J]. Int J Mol Sci, 2019, 20(19):4911.
[5]
DOLCE L G, OHBAYASHI N, SILVA D F C, et al. Unveiling the interaction between the molecular motor Myosin Vc and the small GTPase Rab3A [J]. J Proteomics, 2020, 212: 103549.
[6]
BEAUMONT S, OTERO T F. The response of polypyrrole-DBS electrochemical molecular motors to Na concentration: analogies in cell biology [J]. Electrochem Commun, 2019, 103: 114-119.
[7]
MATSUDA A, LI J, BRUMM P, et al. Mobility of molecular motors regulates contractile behaviors of actin networks [J]. Biophys J, 2019, 116(11):2161-2171.
[8]
DIEDERIK R, CONSTANTIN S, WOJCIECH D, et al. Light-gated rotation in a molecular motor functionalized with a dithienylethene switch [J]. Angew Chem Int Ed Engl, 2018, 57(33):10515-10519.
[9]
JIA Y, LI J B. Molecular assembly of rotary and linear motor proteins [J]. Acc Chem Res, 2019, 52(6):1623-1631.
[10]
PYRPASSOPOULOS S, SHUMAN H, OSTAP E M. Modulation of kinesin′s load-bearing capacity by force geometry and the microtubule track [J]. Biophys J, 2020, 118(1):243-253.
[11]
JIRI P, MICHAL C. Molecular dynamics simulation of the nanosecond pulsed electric field effect on kinesin nanomotor [J]. Sci Rep, 2019, 9(1):19721.
[12]
GUO X Q. The movement of molecular motors: sliding movement of life [J]. Chin J Nat (自然杂志), 2019, 41(1):56-62.
[13]
PENA A, SWEENY A, COOK A D, et al. Structure of microtubule-trapped human kinesin-5 and its mechanism of inhibition revealed using cryoelectron microscopy [J]. Structure, 2020, 28(4):450-457.
[14]
CAO T L, HAN M Z, XU J, et al. Structures and mechanisms of kinesin′s walking [J]. Chin J Biochem Mol Biol (中国生物化学与分子生物学报), 2016, 32(7):734-744.
[15]
HU X Q, LIANG S S, JI M C, et al. Chromokinesin KIF4A inhibits migration of gastric cancer cells [J]. J Shandong Univ (Nat Sci) (山东大学学报:理学版), 2015, 50(11):1-7.
[16]
ZHANG X, WANG Y Y, LIU X M, et al. KIF2A promotes the progression via AKT signaling pathway and is upregulated by transcription factor ETV4 in human gastric cancer [J]. Biomed Pharmacother, 2020, 125: 109840.
[17]
LI H Y, ZHOU X, CHEN Y Q, et al. Expression of KIF3A in different gastric mucosal lesions, metastatic lymph nodes and its relationship with metastasis and prognosis of gastric adenocarcinoma [J]. Cancer Res Prev Treat (肿瘤防治研究), 2018, 45(12):985-990.
[18]
SOUZA L M B D, CARVALHO J, BATES M D, et al. Production of a kinesin-related recombinant protein (Lbk39) from Leishmania braziliensis by Leishmania tarentolae promastigotes and its application in the serodiagnosis of leishmaniasis [J]. One Health, 2019, 8: 100111.
[19]
SHENG L, HAO S L, YANG W X, et al. The multiple functions of kinesin-4 family motor protein KIF4 and its clinical potential [J]. Gene, 2018, 678: 90-99.
[20]
KELLIE A W, STEPHANIE G L, BRANDON M B, et al. An allosteric propofol-binding site in kinesin disrupts kinesin-mediated processive movement on microtubules [J]. J Biol Chem, 2018, 293(29):11283-11295.
[21]
DIETER R K, MICHIO T, NICO S, et al. Role of phosphatidylinositol (4, 5) bisphosphate organization in membrane transport by the Unc104 kinesin motor [J]. Cell, 2002, 109(3):347-358.
[22]
QIN X N, YOO H, CHENG H C M, et al. Simultaneous tracking of two motor domains reveals near simultaneous steps and stutter steps of myosin 10 on actin filament bundles [J]. Biochem Biophy Res Common, 2020, 525(1):94-99.
[23]
BARGER S R, JAMES M L, PELLENZ C D, et al. Human myosin 1e tail but not motor domain replaces fission yeast Myo1 domains to support myosin-I function during endocytosis [J]. Exp Cell Res, 2019, 384(2):111625.
[24]
GARDINI L, ARBORE C, CAPITANIO M, et al. A protocol for single molecule imaging and tracking of processive myosin motors [J]. Methods X, 2019, 6: 1854-1862.
[25]
LIU Y, AN M W, LI X N, et al. Mechanical effect of myosinⅡ on cell mitosis [J]. J Med Biomech (医用生物力学), 2010, 25(2):152-156.
[26]
YIN Y H, GUO Z, CHEN X, et al. Studies on biomechanics of skeletal muscle based on the working mechanism of myosin motors: an overview [J]. Chin Sci Bull, 2012, 57(35):4533-4544.
[27]
WOODHEAD J L, CRAIG R. The mesa trail and the interacting heads motif of myosin Ⅱ [J]. Arch Biochem Biophys, 2020, 680: 108228.
[28]
JIU Y, KUMARI R, FENIX A M, et al. Myosin-18B promotes the assembly of myosin Ⅱ stacks for maturation of contractile actomyosin bundles[J]. Curr Biol, 2019, 29(1):81-92.e5.
[29]
WONSEOK H, CHANGBONG H. Correction to "energetic costs, precision, and transport efficiency of molecular motors" [J]. J Phys Chem Lett, 2019, 10(12):3472.
[30]
KUMAR R, BHARADWAJ L M, LALL A K. Speed and load characterization of actin-myosin nanomotor [J]. Mater Today Proc, 2019, 18: 5488-5493.
[31]
GARDINI L, ARBORE C, PAVONE F S, et al. Myosin V fluorescence imaging dataset for single-molecule localization and tracking [J]. Data Brief, 2019, 25: 103973.
[32]
TSAI T Y C, COLLINS S R, CHAN C K, et al. Efficient front-rear coupling in neutrophil chemotaxis by dynamic myosin Ⅱ localization [J]. Dev Cell, 2019, 49(2):189-205.e6.
[33]
MARK G P, JOHN E C L, RYAN D, et al. In vitro and in vivo pharmacokinetic characterization of mavacamten, a first-in-class small molecule allosteric modulator of beta cardiac myosin [J]. Xenobiotica, 2019, 49(6):718-733.
[34]
EDAMATSU M. Development of an expression system in Tetrahymena inner arm dyneins and motile properties of the single-headed subspecies (Dyh8p and Dyh12p) [J]. Biochem Biophy Res Commun, 2020, 523(1):253-257.
[35]
ZHANG J P. Kinetics study on the processivity of myosin V(肌球蛋白V持续运动特性的动力学研究) [D]. Hohhot: Inner Mongolia University, 2017.
[36]
LI S M, ZHANG J P, WANG Y J, et al. Study on the processivity of four-state myosin Ⅴ [J]. J Inner Mongolia Univ (Nat Sci Ed) (内蒙古大学学报:自然科学版), 2019, 50(2):171-181.
[37]
RENSH H, JUVVADI P R, COLE D C, et al. The class V myosin interactome of the human pathogen Aspergillus fumigatus reveals novel interactions with COPII vesicle transport proteins [J]. Biochemys Bioph Res Commun, 2020, 527(1):232-237.
[38]
LAW S, STOUT M, RENSCH A, et al. Expression of MYOSIN VIIA in developing mouse cochleovestibular ganglion neurons [J]. Gene Expr Patterns, 2020, 35: 119092.
[39]
ORGAZ J L, MOLIST E C, SADOK A, et al. Myosin Ⅱ reactivation and cytoskeletal remodeling as a hallmark and a vulnerability in melanoma therapy resistance [J]. Cancer Cell, 2020, 37(1):85-103.e9.
[40]
WAGNER W, LIPPMANN K, HEISLER F F, et al. Myosin Ⅵ drives clathrin-mediated AMPA receptor endocytosis to facilitate cerebellar long-term depression [J]. Cell Rep, 2019, 28(1):11-20.e9.
[41]
ZHANG L, WANG P, YANG Z Y, et al. Molecular dynamics simulation exploration of the interaction between curcumin and myosin combined with the results of spectroscopy techniques [J]. Food Hydrocolloid, 2020, 101: 105455.
[42]
LIU X, SHU S, BILLINGTON N, et al. Mammalian nonmuscle myosin Ⅱ binds to anionic phospholipids with concomitant dissociation of the regulatory light chain [J]. J Biol Chem, 2016, 291(48):24828-24837.
[43]
LI S L, NICKELS J, PALMER A F. Liposome-encapsulated actin-hemoglobin (LEAcHb) artificial blood substitutes [J]. Biomaterials, 2005, 26(17):3759-3769.
[44]
RACHEL K, NANCY L, MARIO F, et al. Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models [J]. Cell Stress Chaperones, 2020, 25(1):173-191.
[45]
IBUSUKI R, SHIRAGA M, FURUTA A, et al. Collective motility of dynein linear arrays built on DNA nanotubes [J]. Biochem Biophys Res Commun, 2020, 523(4):1014-1019.
[46]
PERREAULT M C, BERNIER A P, RENAUD J S, et al. Corrigendum to “C fragment of tetanus toxin hybrid proteins evaluated for muscle-specific transsynaptic mapping of spinal motor circuitry in the newborn mouse” [Neuroscience 141(2) (2006) 803-816][J]. Neuroscience, 2020, 424: 211.
[47]
ARAGON M A, FLETCHER G, THOMPSON B J. The cytoskeletal motor proteins dynein and MyoV direct apical transport of crumbs [J]. Dev Biol, 2020, 459(2):126-137.
[48]
SCHMIDTS M, HOU Y Q, CORTES C R, et al. TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport [J]. Nat Commun, 2015, 6: 7074.
[49]
TERENZIO M, PIZIO A D, RISHAL I, et al. DYNLRB1 is essential for dynein mediated transport and neuronal survival [J]. Neurobiol Dis, 2020, 140: 104816.
[50]
YOUSAFI Q, AZHAR M, KHAN M S, et al. Interaction of human dynein light chain 1 (DYNLL1) with enterochelin esterase (Salmonella typhimurium) and protective antigen (Bacillus anthraci) might be the potential cause of human infection [J]. Saudi J Biol Sci, 2019, 27(5):1396-1402.
[51]
OSSEMAN Q, GALLUCCI L, AU S, et al. The chaperone dynein LL1 mediates cytoplasmic transport of empty and mature hepatitis B virus capsids [J]. J Hepatol, 2018, 68(3):441-448.
[52]
DALMAU-MENA I, PINO P D, PELAZ B, et al. Nanoparticles engineered to bind cellular motors for efficient delivery [J]. J Nanobiotechnol, 2018, 16(1):33.
[53]
HOING S, YEH T Y, BAUMANN M, et al. Dynarrestin, a novel inhibitor of cytoplasmic dynein [J]. Cell Chem Biol, 2018, 25(4):357-369.e6.
[54]
LAURENS P D M, JORG K, CHRISTIAN O. Nonadiabatic molecular dynamics on graphics processing units: performance and application to rotary molecular motors [J]. J Chem Theory Comput, 2019, 15(12):6647-6659.
[55]
SALEWSKIJ K, RIEGER B, HAGER F, et al. The spatio-temporal organization of mitochondrial F1FOATP synthase in cristae depends on its activity mode [J]. BBA - Bioenergetics, 2020, 1861(1):148091.
[56]
NUSKOVA H, MIKESOVA J, EFIMOVA I, et al. Biochemical thresholds for pathological presentation of ATP synthase deficiencies [J]. Biochem Biophys Res Commun, 2020, 521(4):1036-1041.
[57]
MEGHNA S, ROBERT I, ALASTAIR S G. ATP synthase: expression, purification, and function [J]. Methods Mol Biol, 2020, 2073: 73-84.
[58]
GREG V C, KESHAV D, AVESH C. Does the stromal concentration of Pi control chloroplast ATP synthase protein amount in contrasting growth environments? [J]. Plant Signal Behav, 2019, 14(12):1675473.
[59]
VINOGRADOV A D. New perspective on the reversibility of ATP synthesis and hydrolysis by Fo×F1-ATP synthase(hydrolase) [J]. Biochemistry (Mosc), 2019, 84(11):1247-1255.
[60]
NELLI M, MARC L C, YANG Y S, et al. A mitochondrial megachannel resides in monomeric F1FO ATP synthase [J]. Nat Commun, 2019, 10(1):5823.
[61]
OLGA N, PAVEL B, IVAN G. Assembly of spinach chloroplast ATP synthase rotor ring protein-lipid complex [J]. Front Mol Biosci, 2019, 6: 135.
[62]
MNATSAKANYAN N, LLAGUNO M C, YANG Y S, et al. A mitochondrial megachannel resides in monomeric F1FO ATP synthase [J]. Nat Commun, 2019, 10(1): 5823.
[63]
SALEWSKIJ K, RIEGERA B, HAGER F, et al. The spatio-temporal organization of mitochondrial F1FO ATP synthase in cristae depends on its activity mode [J]. BBA - Bioenergetics, 2020, 1861(1):148091.
[64]
NUSKOVA H, MIKESOVA J, EFIMOVA I, et al. Biochemical thresholds for pathological presentation of ATP synthase deficiencies [J]. Biochem Biophys Res Commun, 2020, 521(4):1036-1041.
[65]
AMINI A, RAHEEM S, STEINER A, et al. Insect venom peptides as potent inhibitors of Escherichia coli ATP synthase [J]. Int J Biol Macromol, 2020, 150: 23-30.
[66]
CHATTERJEE A, PANDEY S, DHAMIJA E, et al. ATP synthase, an essential enzyme in growth and multiplication is modulated by protein tyrosine phosphatase in Mycobacterium tuberculosis H37Ra [J]. Biochimie, 2019, 165: 156-160.
[67]
KAMARIAH N, RAGUNATHAN P, SHIN J, et al. Unique structural and mechanistic properties of mycobacterial F-ATP synthases: implications for drug design [J]. Prog Biophys Mol Bio, 2019, 152: 64-73.
[68]
NARANG R, KUMAR R, KALRA S, et al. Recent advancements in mechanistic studies and structure activity relationship of FoF1 ATP synthase inhibitor as antimicrobial agent [J]. Eur J Med Chem, 2019, 182: 111644.
[69]
GAUBA E, CHEN H, GUO L, et al. Cyclophilin D deficiency attenuates mitochondrial F1Fo ATP synthase dysfunction via OSCP in Alzheimer′s disease [J]. Neurobiol Dis, 2019, 121: 138-147.
[70]
MINAMINO T, KINOSHITA M, NAMBA K. Directional switching mechanism of the bacterial flagellar motor [J]. Comput Struct Biotechnol J, 2019, 17: 1075-1081.
[71]
DEBORAH R A, BRITTNI K R, JEREMIAH J G, et al. A chaperone for the stator units of a bacterial flagellum [J]. mBio, 2019, 10(4):e01732-19.
[72]
ZHU S W, QIN Z, WANG J Y, et al. In situ structural analysis of the spirochetal flagellar motor by cryo-electron tomography [J]. Methods Mol Biol, 2017, 1593: 229-242.
[73]
CHAI Y, YU J, TU Y H, et al. Switching bacterial flagella motor [J]. Biophys J, 2013, 104(2):641a.
[74]
HUGHES L, TOWERS K, STARBORG T, et al. A cell-body groove housing the new flagellum tip suggests an adaptation of cellular morphogenesis for parasitism in the bloodstream form of Trypanosoma brucei [J]. J Cell Sci, 2013, 126(24):5748-5757.
[75]
FERREIRA J L, GAO F Z, ROSSMANN F M, et al. γ-proteobacteria eject their polar flagella under nutrient depletion, retaining flagellar motor relic structures [J]. PLoS Biol, 2019, 17(3):e3000165.
[76]
MIZUNOA K, SLOBODAA R D. Protein arginine methyltransferases interact with intraflagellar transport particles and change location during flagellar growth and resorption [J]. Mol Biol Cell, 2017, 28(9):1208-1222.
[77]
BENEKE T, DEMAY F, HOOKWAY E, et al. Genetic dissection of a Leishmania flagellar proteome demonstrates requirement for directional motility in sand fly infections [J]. PLoS Pathog, 2019, 15(6):e1007828.
2020, Vol. 55 
