Scientists solve puzzle of how kinesin motor molecules walk. Transport within neurons is mediated by multiple motor proteins, many of which are involved in synaptic transmission and axonal trafficking. Numerous studies have revealed the structures and functions of. Rangtp regulates cilium formation and ciliary trafficking. International conference on molecular mechanism of. If there is a membrane protein in the er, it will get budded off while still in the membrane. Each head, consisting of approximately 340 residues, is a motor unit that binds. Motor protein heads have very similar amino acid sequences, inferring the same evolutionary origin. Kinesin superfamily proteins kifs are key players or hub proteins in the intracellular transport system, which is essential for cellular function and morphology. Cooperativity of motor proteins is essential for intracellular transport. Unidirectional transport even though a single motor molecule can power processive motion, transport in cells is often driven by more than one motor 1. Kinesin superfamily protein member 4 kif4 is localized to. Kinesin superfamily proteins also known as kifs transport various cargos in both anterograde and retrograde directions through the interaction with different adaptor proteins. Researchers identify proteins that direct intracellular.
Active and advective transport are thus intrinsically coupled as related, yet different representa. Kinesins and cytoplasmic dyneins play essential roles in intracellular transport such as axonal transport and in the formation of. Engelke 1, michael winding 2, yang yue 1, shankar shastry 3,4, federico teloni 1, sanjay reddy 1, t. Kinesin superfamily proteins also known as kifs are important molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mrnas. The organelles of the secretory pathway are involved in the sorting of proteins to a variety of intracellular membrane compartments and the cell surface. The roles of kinesin and dynein superfamily proteins the molecular motor conference 2007 at grand hotel new oji in tomakomai, hokkaido, japan organizer nobutaka hirokawa august 2326, 2007 abstracts of papers presented at the 56th fujihara seminar as. Abstract using various molecular cell biological and molecular genetic approaches, we identified kinesin superfamily proteins kifs and characterized their significant functions in intracellular transport, which is fundamental for cellular morphogenesis, functioning, and survival. The vesicles with properly foled proteins will then fuse with the golgi apparatus. Kinesin superfamily proteins kifs are motor proteins that transport membranous organelles and macromolecules fundamental for cellular functions along microtubules. Microtubules roads made of proteins extend throughout a cell for motor. Coupling between motor proteins determines dynamic behaviors. Engineered kinesin motor proteins amenable to small molecule. Kinesin superfamily motor proteins and intracellular transport. The proteins are extensively quality controlled for purity 85% and biological activity microtubule activated atpase activity must be at least comparable to published data.
The net movement of proteins from the endoplasmic reticulum er to the golgi apparatus represents one form of intracellular transport through this mode of vesicle budding. Overexpression of kinesin superfamily motor proteins in. Kinesin, dynein, and myosin are the three types of motor proteins found. The motor proteins kinesin and dynein exist to transport biological payloads, such as proteins, organelles, and vesicles, along microtubule pathways, and provide forces to drive motion of flagellar structures and cilia. Transport proteins are vital to the growth and life of all living things. One advantage of cargo transport by several motors is a higher velocity if the cargo experiences a high viscosity8,12. Experiments with vesicles containing n methyldaspartate nmda receptor 2b nr2b subunit show that they are transported along microtubules by kif17, a neuronspecific molecular motor in neuronal dendrites. Posttranslational modification of the cargobinding domain of the light and heavy chains of kinesin has been shown to regulate transport, but less is known about how modifications of the motor domain affect transport.
We showed that kifs not only transport various membranous. Kinesin proteins make up a large superfamily of molecular motors, known as kinesin superfamily proteins kifs. Structure, function, and dynamics hirokawa, nobutaka. Kinesin and dynein superfamily proteins and the mechanism of. The expansion of the kinesin superfamily in plants was exemplified in a recent study tagging and tracking the intracellular distribution of a stunning number of 43 kinesins in the moss. Kinesins were discovered as mtbased anterograde intracellular transport motors. If these chaperone proteins fail to fold er proteins properly, the misfolded proteins will be degraded. Kinesin superfamily proteins kifs are motor proteins that convert chemical energy, typically in the form of atp, into mechanical force. These proteins bind to vesicles and organelles and use energy from atp to move them along the microtubule or microfilament network. However, motor protein tails vary significantly in their amino acid sequence, showing the variety of cargo to which different klps can bind to.
Proteins contain structural information that targets them to their correct destination and many targeting signals have now been defined. Kinesins and cytoplasmic dyneins play essential roles in intracellular transport such as axonal transport and in the formation of the spindle apparatus and the separation of the chromosomes during mitosis and meiosis. Results designing kinesins amenable to smallmolecule inhibition. Multiple antlike transport of neuronal cargo by motor proteins date.
Functions of kinesin superfamily proteins in neuroreceptor. The heterotrimeric kinesin ii, consisting of the kinesin like protein kif3a3b heterodimer and kinesin associated protein kap3, is highly conserved across species from the green alga chlamydomonas to humans. Molecular motors of the kinesin superfamily contain a kinesin motor domain attached to familyspecific sequences for cargo binding, regulation, and oligomerization. The kinesin superfamily proteins kifs have been shown to transport membranous organelles and protein complexes in a microtubule and atpdependent manner. Is this walking protein what happiness really looks like. Kinesin 1 is a processive motor that moves cargo, such as an organelle, continuously toward the plus end of a microtubule. Kinesin superfamily motor proteins and intracellular. Molecular motors, such as kinesin 1, contain two motor domains so they can walk processively take many steps per encounter along a microtubule track.
Membrane mediated motor kinetics in microtubule gliding assays. However, the nomenclature of kifs has not been clearly established, resulting in various designations. The kinesin superfamily protein kif5 transports mrnas such as calciumcalmodulindependent kinase ii. The kinesin tree was built from a sequence alignment of 144 kinesin motor domains from 31 species using the heuristic search method of paup v. Theoretical investigations of the role of mutations in. Motor proteins attach to cargoes and move them to various locations in the celk vesicular organelle transport, flagellar beating, axonal transport, chromosome segregation, and muscle contraction are afew of the motility processes motor proteins perform goldstein, 1993. Kinesin superfamily proteins kifs in intracellular transport. Kinesin and dynein superfamily proteins and the mechan ism of organelle.
Intracellular organelle transport is essential for morphogenesis and functioning of the cell. Structure of a kinesintubulin complex and implications. The founding member of this superfamily, kinesin1, was isolated as a heterotetrameric fast axonal organelle transport motor consisting of 2 identical motor subunits khc and 2 light chains klc via microtubule affinity purification from neuronal cell extracts. Kinesin superfamily proteins kifs participate in the establishment and maintenance of neuronal polarity by selectively transporting various proteins and vesicles to either the axon or dendrites. Kinesin superfamily proteins kifs are microtubuledependent molecular motors that serve as sources of force for intracellular transport and cell division. Based on the high conservation of the motor domain across the kinesin superfamily and the development of two different inhibition strategies, we suggest that these strategies can be used to generate inhibitable versions of any kinesin motor of interest. Intracellular transport is fundamental for cellular function, survival and morphogenesis.
Intracellular transport is driven by molecular motors that carry cargoes along cytoskeletal tracks. International conference on molecular mechanism of intracellular transport. Kinesin superfamily proteins and the regulation of. Coupling of active motion and advection shapes intracellular. For example, proteins that are transported within the. Kinesin and dynein superfamily proteins and the mechanism of organelle transport. A transport protein variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein is a protein that serves the function of moving other materials within an organism. Polarity of microtubules and properties of nkinesin.
The final element that is needed for a vesicle transport system is motor proteins, as indicated in figure 9. Kinesin superfamily proteins and their various functions. Selective transport is accomplished by direct interaction of the kif17 tail with a pdz domain of mlin10 mint1x11, which is a constituent of a large protein complex including mlin. A kinesin is a protein belonging to a class of motor proteins found in eukaryotic cells kinesins move along microtubule mt filaments, and are powered by the hydrolysis of adenosine triphosphate atp thus kinesins are atpases. Compared with other cell types, in which only a short distance of transport is required to. Kinesin superfamily proteins also known as kifs are important molecular motors that directionally. The tree is one of six optimal trees that were found in 530 treebuilding trials and is. Randy schekmans research is focused on the process of membrane assembly, vesicular transport, and membrane fusion among organelles of the secretory pathway. The nematode caenorhabditis elegans genome encodes 21 members of the kinesin family, which show significant homology to their mammalian orthologs.
Intracellular cargo transport by singleheaded kinesin. Neuronal polarity and the kinesin superfamily proteins. Furthermore, kinesin, along with dynein, especially form the mitotic spindle while myosin forms both the cytoskeleton and the contractile filaments of the muscle cells. Kinesin superfamily proteins kifs are motor proteins that transport membranous organelles and macromolecules. Feb 28, 2004 kinesins and kinesinrelated proteins make up a large superfamily of molecular motors that transport cargoes such as vesicles, organelles e. Spatial patterning of kinesin1 and dynein motor proteins. Association of the kinesin superfamily motor protein kif1balpha with postsynaptic density95 psd95, synapseassociated protein 97, synaptic scaffolding molecule psd95discs largezona occludens1 proteins. At present, we found that exogenous mir203 increased pigmentation and protein expression levels of the melanoma antigen recognized by t cells melanasmart1s andor tyrosinase tyr in the human melanoma cells tested. Motor proteins are the driving force behind most active transport of proteins and vesicles in the cytoplasm.
Our research is devoted to a molecular description of the process of membrane assembly and vesicular traffic in eukaryotic cells. As shown by recent data, the basic principles of intracellular transport are highly conserved, and motor proteins constitute a common molecular machinery for intracellular transport in neurons as well as in other types of cells 65, 71, 96, 101, 229. Subsequent related proteins of the same superfamily are called kinesinlike proteins klp. As shown by recent data, the basic principles of intracellular transport are highly conserved, and motor proteins constitute a common molecular machinery for intracellular transport in neurons as well as in other types.
The main difference between kinesin and myosin is that the kinesin moves on microtubules while the myosin moves on microfilaments. Based on motor domain sequence homology and placement of the motor domain in the protein, the c. Although their motion is unidirectional, they often cause bidirectional movement by different types of motors as seen in organelles. Longdistance transport in eukaryotic cells is driven by molecular motors that move along microtubule tracks. Combined with kinetic analyses, the high resolution structure of kinesin 1 bound to a tubulin dimer offers a muchanticipated view of the motor microtubule interface that. Whereas plus enddirected motors promote spindle pole separation early in mitosis, this activity must be balanced in metaphase by an opposing force, to prevent excessive increase in spindle size. Intracellular transport is essential for morphogenesis and functioning of the cell. Kifs are a class of microtubulebased mechanochemical enzymes with a conserved motor domain for adenosine triphosphate atpdependent. Microtubule motor proteins and the mechanisms of synaptic. Intracellular transport and kinesin superfamily proteins, kifs. Intracellular sorting and transport of proteins sciencedirect. Motor domain phosphorylation modulates kinesin1 transport. Structure, cargo and disease intracellular organelle transport is essential for morphogenesis and functioning of the cell.
Abstractintracellular transport along microtubules enables cellular cargoes to efficiently reach the extremities of large, eukaryotic cells. Kinesin family member 15 kif15 is a member of the kinesin superfamily of proteins, which promotes cell mitosis, participates in the transport of intracellular materials, and helps structural. Most kifs have these domains in the nh 2terminal region, while others have. Firstly, factin polymers form microfilaments polar intracellular tracks for kinesin motor proteins, allowing the transport of vesicles, organelles and other cargo. Kinesin is part of the microtubule mtbinding motor protein superfamily, which exerts crucial functions in cell division and intracellular transport in different organelles. Conserved catalytic motor domains that involve an atpbinding sequence and a microtubulebinding sequence are indicated in purple. Microtubulebased motors of the kinesin superfamily are involved in intracellular transport, mitosis and meiosis, control of microtubule dynamics and signal transduction pathways1.
Intracellular transport and kinesin superfamily proteins. Motor proteins regulate the properties of the spindle apparatus by a complicated balance of forces fig. However, in vitro assessments of such cellular functions are still inadequate owing to the experimental limitations in precisely patterning multiple motors. Enzymes modify microtubules by adding or removing different molecules from their surfaces. The kif superfamily is also the first large protein family in mammals whose constituents have been completely identified and confirmed both in silico and in vivo. Engineered kinesin motor proteins amenable to small molecule inhibition martin f. Their roles in transport in axons and dendrites have been studied extensively, but kifs are also used in intracellular transport in general. Kinesin superfamily proteins, usually refer as kifs or kinesin, represent a class of motor proteins, which widely involve in intracellular transport of proteins, organelles, and rna granules, etc. Various molecular cell biology and molecular genetic approaches have indicated significant roles for kinesin superfamily proteins kifs in intracellular transport and have shown.
The best prominent example of a motor protein is the muscle protein myosin which motors the contraction of muscle fibers in animals. Using various molecular cell biological and molecular genetic approaches, we identified kinesin superfamily proteins kifs and characterized their significant functions in intracellular transport, which is fundamental for cellular morphogenesis, functioning, and survival. Multiple antlike transport of neuronal cargo by motor proteins. Molecular motor proteins of the kinesin superfamily. To execute these various activities, different kinesin family members have distinct protein. Kinesin and dynein superfamily proteins and the mechanism.
Molecular motor proteins of the kinesin superfamily proteins kifs. Active transport by kinesin and dynein provides a faster and more efficient mode of intracellular transport than diffusion. Molecular basis for specific regulation of neuronal kinesin3. Microrna203 regulates melanosome transport and tyrosinase. Intracellular transport is thus fundamental to cellular morphogenesis and functioning.
The biochemical and biophysical properties of the kinesin motor domain have been widely studied, yet little is known. Kinesin superfamily proteins kifs share a common atpbinding motor domain, fused to divergent tail domains that specify intracellular localization and function. In eukaryotic cells members of the kinesin family mediate intracellular transport by carrying cellular cargo on microtubule tracks. Intracellular cargo transport can arise from passive diffusion, active motordriven transport along cytoskeletal.
While it would take more than 200 years for a small vesicle to diffuse from the cell body to the growing tip of a onemeter long axon, transport by a kinesin allows delivery in one week. The heterotrimeric kinesin ii, consisting of the kinesin like protein kif3a3b heterodimer and kinesin associated protein kap3, is highly conserved across species between the green alga chlamydomonas and humans. Many kinesins utilize chemical energy derived from atp hydrolysis to propel directional transport of various cargoes along the microtubule mt cytoskeleton. Recent studies have revealed new roles of kifs as microtubule stabilizers and depolymerizers, and these activities are fundamental to cellular morphogenesis and mammalian development. Recent studies have revealed that mrnas are transported by molecular motors.
Intracellular transport, kinesin motor proteins transport molecules moving across microtubules, 3d illustration. Kinesin superfamily proteins kifs comprise a large group of motor proteins whose primary role is the anterograde axonal transport and intraneuronal transport of protein cargoes through association with. Jul 05, 2006 the targeting of mrnas to neuronal dendrites is an important protein sorting mechanism. All kinesin superfamily protein, kif, genes in mouse and. Kinesin superfamily kifs were a group of proteins featured to be microtubulebased motors and functioned as intracellular transporters that directionally transport various cargos, including. Intracellular transport is essential for appropriate cellular morphology and function. Motor proteins are also interesting from a physical point of view because they do what no manmade. Recent studies indicate that kifs regulate the trafficking of nmda receptors, ampa receptors, kainate receptors, and gaba receptors and thus play important roles in. Engineered kinesin motor proteins amenable to smallmolecule. The founding member of this family was identified as the third nkinesin table 1. What is the difference between kinesin and myosin pediaa. The active movement of kinesins supports several cellular functions including mitosis, meiosis and transport of cellular cargo, such as in axonal transport. Kinesin motor domains, kinesin, microtubuleactivated atpase, kinesin motility, mcak kinesin motor domain protein, mcak, mcak kinesin. They act upon microtubules to move vesicles and organelles within cells, cause the beating of flagella and cilia, and act within the mitotic and meiotic spindles to segregate replicated chromosomes to progeny cells.
There are many types of motor proteins in living organisms, but one of the most studied motors is a conventional kinesin, or kinesin 1, which is a member of a kinesin superfamily of motor proteins. Motor proteins have essential biological functions such as driving the contraction of muscle, the beating of sperm and cilia, and the transport of intracellular cargoes. We discovered most of the kinesin superfamily motor proteins, kifs, 45 genes in mammals, elucidated their molecular structures and functional roles by molecular cell biology, molecular genetics, biophysics and structural biology and successfully disclosed the mechanism of intracellular transport fundamental for neuronal functions. Disruptions in microtubule motor transport are associated with a variety of neurodegenerative diseases. The role of kinesin family proteins in tumorigenesis and. Kinesin motor proteins that drive intracellular transport share an overall architecture of two motor domaincontaining subunits that dimerize through a coiledcoil stalk. Actin is a component of the cytoskeleton and links to.
Chapter 15 intracellular compartments and protein transport. Molecular motor proteins of the kinesin superfamily proteins. Intracellular cargo transport by singleheaded kinesin motors. The primary aim of the hoogenraad research lab at the university of utrecht, the netherlands, is to understand how intracellular protein transport underlies the. Since the er is the site of protein synthesis, it would serve as the parent organelle, and the cis face of the golgi, where proteins and signals are received, would be the.
Dimerization allows kinesins to be processive motors, taking many steps along the microtubule track before detaching. Microrna mir203 is known to be downregulated and to act as an antioncomir in melanoma cells. Kinesins and kinesinrelated proteins make up a large superfamily of molecular motors that transport cargoes such as vesicles, organelles e. In this process, transport vesicles deliver soluble cargo proteins, as well as the proteins and lipids that are part of the vesicle membrane.
Misfolded er proteins are properly folded by chaperone proteins. Intracellular transport, molecular motors, kifs and related. Kinesins and kinesin related proteins make up a large superfamily of molecular motors that transport cargoes such as vesicles, organelles e. Genes, structure, dynamics, functions and diseases nobutaka hirokawa department of cell biology and anatomy, graduate school of medicine, university of tokyo introduction cells transport and sort various proteins and lipids following synthesis as distinct kinds of.
Inversely, treatment with an inhibitor of mir203 downregulated the expression. The two motor domains alternate their catalytic activities so that one of them is always attached to the track. Microtubules serve as a rail on which motor proteins, such as kinesin and dynein superfamily proteins, convey their cargoes. Cells transport and sort proteins and lipids, after their synthesis, to various destinations at appropriate velocities in membranous organelles and protein complexes. May, 2005 motor proteins haul molecular cargo within cells by traveling along protein fibers called microtubules. Signal sequence composition the typical sorting signal on a protein is a continuous stretch of animo acid sequence, usually 1560 animo acids long. Molecular motors known as the kinesin superfamily proteins kifs have been shown to transport organelles. Kinesin superfamily motor protein kif17 and mlin10 in. Pdf the novel functions of kinesin motor proteins in plants.