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Cytoskeleton Molecular Motors: Structures and Their Functions in Neuron Qingpin Xiao1,2, Xiaohui Hu1, Zhiyi Wei2, Kin Yip Tam1,

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Cytoskeleton Molecular Motors: Structures and Their Functions in Neuron Qingpin Xiao1,2, Xiaohui Hu1, Zhiyi Wei2, Kin Yip Tam1, Int. J. Biol. Sci. 2016, Vol. 12 1083 Ivyspring International Publisher International Journal of Biological Sciences 2016; 12(9): 1083-1092. doi: 10.7150/ijbs.15633 Review Cytoskeleton Molecular Motors: Structures and Their Functions in Neuron Qingpin Xiao1,2, Xiaohui Hu1, Zhiyi Wei2, Kin Yip Tam1, 1. Faculty of Health Sciences, University of Macau, Taipa, Macau, China 2. Department of Biology, Southern University of Science and Technology, Shenzhen, 518055, China Corresponding author: Tam, K.Y. ([email protected]); Tel.: +853-88224988; fax: +853-88222314 © Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions. Received: 2016.03.24; Accepted: 2016.05.28; Published: 2016.07.18 Abstract Cells make use of molecular motors to transport small molecules, macromolecules and cellular organelles to target region to execute biological functions, which is utmost important for polarized cells, such as neurons. In particular, cytoskeleton motors play fundamental roles in neuron polarization, extension, shape and neurotransmission. Cytoskeleton motors comprise of myosin, kinesin and cytoplasmic dynein. F-actin filaments act as myosin track, while kinesin and cytoplasmic dynein move on microtubules. Cytoskeleton motors work together to build a highly polarized and regulated system in neuronal cells via different molecular mechanisms and functional regulations. This review discusses the structures and working mechanisms of the cytoskeleton motors in neurons. Key words: Cytoskeleton motors; Myosin; Kinesin; Cytoplasmic dynein; Neuron Introduction Actin-based motors A neuron cell is highly polarized, composing of a According to their gene sequence homology, cell body, an axon and dendrites. Macromolecules, myosin can be classified into 35 classes in eukaryote such as proteins and RNA, are synthesized in [1]. Mammals have 40 myosin genes, whose neuronal cell body, and are then transported to the expression products fall into 13 classes [2]. Figure 1 axon or dendrites. Cytoskeleton motors are vital to shows the selected myosin families, which have been transport cargos in the biological processes by using reported and expressed in neuronal cells [3,4]. cytoskeleton as walking tracks and hydrolyze ATP to Myosins compose of three common domains [5]: (1) provide mechanical energy. Myosin is one the N-terminal motor domains that interact with actin superfamily of cytoskeletal motors, walking along the and hydrolyze ATP to generate force [6], (2) the neck F-actin filaments. Kinesin and Dynein are both domains or lever arms that transduce and amplify the microtubule motors, walking towards microtubule’s force generated by motor domain [7,8] and (3) the tail plus-end and minus-end directions respectively. The domains offer specific binding sites for different dysfunction of these motor proteins in neuron system cargos [9]. is related to many human neuronal diseases. In this The motor domain of myosin has an work, we review the structural and functional actin-binding site and a nucleotide-binding site, characteristics of cytoskeleton motors and discuss the which are mutually exclusive. Following the motor roles of cytoskeleton motors in neuronal polarization, domain is lever arm, which usually contains some IQ development and neurotransmission processes. motifs (consensus sequence IQxxxRGxxR) for Finally, some possible future directions of calmodulin (CaM) or calmodulin-like proteins cytoskeleton motors study will be highlighted. binding [10,11]. The numbers of IQ motifs vary among different myosin classes. The length of lever http://www.ijbs.com Int. J. Biol. Sci. 2016, Vol. 12 1084 arm determines the step size along actin. The most in N-terminus, the motor domain of kinesins can be essential difference among myosin motor proteins lies found in their N-terminal (N-type), middle (M-type), in their C-terminal globular tail domain (GTD). This or C-terminal (C-type) region [18]. On microtubule, domain recognizes various cargos through direct N-type kinesin moves to the plus end of microtubule, interactions or via adaptor proteins. Usually, GTD C-type kinesin moves to minus end of microtubule binds to the adaptor protein, which can interact with and M-type kinesin can destabilize microtubule tracks organelle-specific Rab family GTPase protein and [19]. The energy supplying for kinesin processive therefore link to the specific organelle or vesicle motility comes from hydrolyzing ATP in the motor [12,13]. domain. Another microtubule-based motor is cytoplasmic Microtubule-based motors dynein (Figure 2B). Compared to myosin and kinesin, Kinesins (also referred to as KIFs) propel cargos dynein is larger in size with more complicated along the microtubule. There are about 45 KIF genes composition and its working mechanisms are not well in mammal genome [14]. A standard kinesin understood. The motor domain of dynein is located in nomenclature system had been developed for the C-terminal region, while tail domain is situated in the kinesin family members based on phylogenic analysis N-terminal region. The motor domain composes of six [15]. Accordingly, the kinesin proteins can be ATPases associated with diverse cellular activities classified into 14 subfamilies, namely kinesin 1 to (AAA) domains. The six AAA domains arrange in a kinesin 14. Figure 2A gives representative kinesin of large doughnut-shape ring [20,21]. AAA1 and AAA3 each family found in neuron [16]. All kinesins contain are responsible for ATP binding and hydrolysis, a highly conserved globular motor domain AAA2 and AAA4 play essential regulatory roles comprising a microtubule-binding site and an [22,23]. The function of AAA5 and AAA6 is not clear, ATP-binding site as well as a diverse tail domain, because they lacked the required ATP-binding which is responsible for cargo recognition and residues and exhibited other functions [21]. Extended binding via the adaptor or scaffolding proteins [17]. from AAA4 domain is an antiparallel coiled-coil Unlike myosin whose motor domain is always located region, at the tip of which is the microtubule-binding Figure 1. Schematic Diagrams of Myosin superfamily representations in neuron. Different myosins possess conserved N-terminal motor domains and diverse C-terminal tail regions. The neck domain binds to calmodulin or calmodulin-like light chains. http://www.ijbs.com Int. J. Biol. Sci. 2016, Vol. 12 1085 domain. Microtubule-binding domain, coupled with intermediate chain (LIC), light chain 8 (LC8), ATP-hydrolysis cycle, moves the protein towards roadblock (also known as LC7) and T-complex minus-end microtubule cytoskeleton. The dynein tail testis-specific protein 1 (TCTEX1). These dynein domain is responsible for dynein homodimerization subunits can interact with adaptor proteins to form and serves as binding sites with other subunits of bridges [24-27]. With these bridges, dynein tail dynein, including intermediate chain (IC), light domain can thus carry the target cargos. Figure 2. Schematic Diagrams of Microtubule-based motor proteins. (A) Kinesin superfamily representations in neuron. Like myosins, kinesins have conserved motor (head) domains and diverse tails. According to the positions of the motor domain, kinesins can be grouped into N-type, M-type and C-type kinesins. (B) Cytoplasmic dynein. The cytoplasmic dynein consists of C-terminal motor domain and N-terminal tail domain. The tail domains not only homodimerize the dynein heavy chains (purple color), but also recruit five other subunits (LIC, IC, LC8, LC7, TCTEX1) to accomplish dynein assembly. http://www.ijbs.com Int. J. Biol. Sci. 2016, Vol. 12 1086 Figure 3. Structural characteristics of cytoskeleton motors. The graphics of 3D views were drawn by PyMOL. (A) Complex structure of myosin VIIa/Sans. Cartoon representation indicates Sans-CEN1 domain binds to myosin VIIa-FERM domain which consists of F1, F2 and F3 lobes. (B) Structure of KIF13B-FHA domain bound to CENTA1. Cartoon diagram shows KIF13B-FHA domain interacts with dimerized CENTA1 PH1 and ArfGAP domains. neuroepithelia stereocilia of the inner ear. Based on Structural biology and cytoskeleton the current study, we can further explore how these motors in neuron mutations individually impact on these interactions. A large number of structural studies have For example, some mutations may function to weaken greatly enhanced our understanding of neurological the interaction, while others may involve in functions of many cytoskeleton motors. We regulation of other partners or signal pathways. summarize a few recent cases as examples to During axonal development, Phosphatidy- highlight the power and uniqueness of structural linositol (3,4,5)-trisphosphate (PIP3)-containing biology in uncovering the molecular mechanisms of vesicles function as the polarization factor, and need cytoskeleton motors. to be transported away from the soma to the tip of Many mutations in cytoskeleton motor proteins axon (more details will be given later). Kinesin III directly lead to diseases and aberrant developments. family KIF13B binds to PIP3 by using Centaurin-α1 In neuron system, mutations found in myosin VIIa tail (CENTA1) as adaptor protein to undertake the region result in the neuron disease named Usher anterograde transport in vivo [32,33]. Structure of syndrome I (USH1), which is characterized by KIF13B-CENTA1 complex had been solved in the deafness and visual impairment [28,29]. presence of
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