Molecular Motors In Neurons

Each motor protein complex - kinesin, dynein, and myosin - consists of multiple domains or accessory subunits. All motors are enzymes that convert chemical energy stored in adenosine triphosphate (ATP) into molecular motion, thereby producing force upon the associated cytoskeletal polymer. Typically, the

ATPase function is mediated by the heavy chain of the respective motor protein complex, whereas accessory intermediate and light chains are specialized for self-assembly or interaction with molecular cargo. However, individual heavy chains also have been shown to directly interact with cargo molecules.

Kinesins form a large protein family, known as kinesin superfamily (KIF) with 45 members in mice and humans5. Many KIFs are primarily expressed in the nervous system, but KIFs are generally expressed in other tissues and mediate a large variety of intracellular transport. The first kinesin to be discovered is known as conventional kinesin and corresponds to KIF5. On the basis of the positions of their motor domains, three types of kinesins have been classified: the amino (N)-terminal motor types (^-kinesins), the middle motor types (M-kinesins) and the carboxy (C)-terminal motor types (C-kinesins)5. ^-kinesins and m-kinesins generally move toward the plus end of microtubules, and the latter also depolymerize microtubules. In contrast, C-kinesins move toward the microtubule minus end. KIFs often exist as tetramers of two heavy chains, consisting of motor, neck, stalk, and tail domains and two light chains, all of which can be involved in cargo interactions. The globular motor domain shared by all KIFs displays high degrees of homology and contains a microtubule-binding sequence and an ATPase-binding site. On the other hand, stalk and tail domains of KIFs are characterized by unique sequences. The diversity of these cargo-binding domains allows transport of numerous different cargoes. KIFs either function as monomeric proteins or form both homo- and heterodimers with other KIF superfamily members. The transport velocity of KIFs is consistent with the speed of fast axonal transport in vivo, which varies from 0.2 to 1.5 p.m s-1 3. Depending on the cargo to be transported, some KIF-containing transport complexes are recruited in the range of p.m min-1. KIF5 family members transport a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-containing vesicles to dendrites6. In this transport complex, the glutamate receptor interacting protein GRIP1 couples AMPA receptors with the carboxy (C)-terminal tail of KIF5 (Figure 13.2).

Figure 13.2. Schematic Representation of Microtubule-Dependent Transport Complexes. (A) Kinesin-mediated anterograde transport of excitatory AMPA-type glutamate receptors. (B) Dynein-mediated retrograde transport of inhibitory glycine receptor (GlyR). Adaptor proteins (GRIP1 and gephyrin, respectively) connect the motor complex with neurotransmitter receptors that represent integral membrane proteins of transport vesicles.

Figure 13.2. Schematic Representation of Microtubule-Dependent Transport Complexes. (A) Kinesin-mediated anterograde transport of excitatory AMPA-type glutamate receptors. (B) Dynein-mediated retrograde transport of inhibitory glycine receptor (GlyR). Adaptor proteins (GRIP1 and gephyrin, respectively) connect the motor complex with neurotransmitter receptors that represent integral membrane proteins of transport vesicles.

Dyneins are microtubule-based motor proteins consisting of a multisubunit complex, which contains two gigantic heavy chains of about 380 kDa and a variable number of associated polypeptides7. The heavy chain mediates ATP binding and microtubule attachment via a carboxy-terminal coiled coil stalk. Each heavy chain interacts with certain intermediate and light chains, allowing construction of a wide variety of different dyneins with many common features, but specialized for individual functions. Cytoplasmic dynein associates with the protein complex dynactin and associated proteins such as p150Glued and dynamitin. Although dynamitin often mediates the interaction between cytoplasmic dynein and its cargoes, some cargoes bind the complex by direct interaction with dynein light chains. Dynein retrogradely transports glycine receptors (GlyRs) in neurons. The transport adaptor that couples GlyR-containing vesicles with the dynein motor complex is gephyrin, a GlyR-binding protein, originally described at postsynaptic sites8,9 (Figure 13.2).

Myosins move along actin filaments and represent a diverse protein family of more than 15 members with one or two motor domains and one or more light chains10. The myosin heavy chain consists of the catalytic domain, including actin and ATP-binding sites, and forms a long a-helix and a globular tail, the former of which interacts with a number of light chains that wrap around and stabilize the helical structure. Some light chains bind divalent cations, such as calmodulin, which serves as myosin light chain. Myosin V dimerizes and forms a two-headed protein that moves toward the barbed or plus end of actin filaments. Furthermore, myosin Va is one of the fastest myosins tested, which moves at a rate of about 0.4 p.m s-111.

Defeat Drugs Death

Defeat Drugs Death

This Book Is One Of The Most Valuable Resources In The World When It Comes To Helpful Info On Avoiding And Beating A Fatal Drug Addiction!

Get My Free Ebook


Post a comment