Examinine functions of myosin II and motor proteins in eukaryotic

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Use typical cellular examples to demonstrate the role these motor proteins play when they move along their specific track.

Introduction

Movement is an important characteristic in a cells life; they need active movement to migrate around in their environment and to carry out intracellular motility activities. Motor proteins have been evolved to create mechanical power needed for movement. They are enzymes that transform chemical energy, using ATP hydrolysis as an energy source, into mechanical forces to propel themselves along a designated track [1] [2]. This type of cellular movement is used in muscle contraction, cell migration, differentiation, transport of subcellular component and cytokinesis [2].

The myosin family are motor proteins, which use enzymes in the motor domain to hydrolyse ATP producing changes in structure, that help it move along actin tracks. Myosin II is the most common member of the myosin family and is found in muscles used for muscle contraction [1] [2]. The kinesin family also use ATP hydrolysis and conformational changes for movement but they move along a microtubule track. Cytosolic Kinesin (Kinesin I) is the first member of kinesin family and is used in movement of organelles inside the cell [3].

Structural Comparison

The structure of Myosin II and cytosolic Kinesin are very similar in that they both have two equal heavy polypeptide chains arranged into three domains. The chain is in alpha helical arrangement, with 2 of the helices twisting around each other to form a coiled coil, the molecule is therefore a dimer [2] [3]. Ref to fig. 1 and 2.

The motor domains of both motor proteins are a globular portion of the N terminal of the heavy polypeptide chain. In myosin II it contains 750 amino acids (molecular weight of 80kDa) [1] [2] [5] whereas kinesin contains only 300 amino acids [3]. The myosin II motor region contains actin and ATP binding sites, but kinesin motor region contains ATP and microtubule binding sites [3]. In both motor proteins the motor region is the most conserved part of the molecule because it is the most important part of the molecule involved in the binding of ATP and linear track [2].

The neck domain is the next region along as it lies adjacent to the motor domain. It is there to connect the motor domain to the tail domain and is important in regulating and generating movement. It is only single stranded so it has a low molecular weight (about 20kDA in myosin II) [1] [2] [5] and made of only 50 amino acids in kinesins. In myosin II this is where the 4 light chains are found, 2 different types of chains on each head domain [2] [3].

The final domain of these motor proteins is the tail domain and is found in the C-terminal of the heavy polypeptide chain. It is here where the 2 alpha helices twist around each other to form coiled coil. Myosin II has a heptad repeat which makes the 2 alpha helices form a coiled coil; (HXXHXXX) ⁿ, where H is hydrophobic amino acid and X is any amino acid [2]. In kinesin the C-terminal of the heavy chain is globular and forms non covalent interactions with light chains. This distinctive region on the tail helps kinesin bind with intracellular organelles [3].

Movement Comparison

Motor proteins use ATP hydrolysis to produce conformational changes in the binding site on the motor domain to form interactions with the linear protein filament tracks, causing the protein to move along its track. This creates a cycle of binding and releasing of the motor protein with its track to propel forward to a new binding site [1]. Myosin II and kinesin both uses two distinct mechanochemical cycles to produce movement.

Myosin II movement along actin is produced by flexion of the neck region acting as a lever arm [2] [4]. The single alpha helical structure of neck is stabilised by the 2 light chains [1]. This arrangement is important in magnifying structural changes, as the transduction of chemical energy from ATP hydrolysis causes small rotations at the converter domain which helps swing the alpha helix of the neck needed for motion [1] [2]. The binding affinity for actin also changes when ATP attaches causing myosin to bind and release the actin at different points along the filament [1]. The myosin molecule moves towards the barbed (positive) end of the actin molecule. At the start of cross bridge cycle the myosin motor region is bound to the actin filament [1] [4] [5]. When ATP binds to the motor region a conformational change occurs which reduces actin affinity and releasing it. The binding site with ATP bound has a larger conformational change which moves the head forward. ATP hydrolysis occurs with ADP and inorganic phosphate still connected to the motor domain. When the motor region binds to a new site on actin filament the inorganic phosphate gets released which strengthens the interaction. This is where the power stroke occurs as ADP gets released the shape of the motor region changes back to its normal state. The motor region is in a rigor configuration, because it is tightly bound to actin [1] [2] [4] [5]. Ref to fig 3.

This can be used in striated muscle fibres to cause contraction, the movement of myosin II along actin causes the sarcomeres to shorten and muscles to contract. Myosin II molecules bind with others using the heavy polypeptide region to form thick filaments which slides along actin filaments in sliding filament theory [1]. Myosin II doesn't move processively in skeletal muscles, as the process of cross bridge cycle shows that there are continual binding and releasing of the actin molecule in order to execute a power stroke for an effective muscle contraction [1]. Ref to fig 4.

Fig 4. Labelled diagram of sarcomere in skeletal muscles [1]. A sarcomere is a contractile unit found in myofibrils of skeletal muscle. There are many sarcomeres arranged along the whole length of myofibril. Each sarcomere is separated from each other by Z lines. The thin filaments made from actin and other proteins are attached to the Z line via the plus end of the molecule, which are capped using CapZ preventing depolymerisation. The minus end is also capped with tropomodulin and point toward the middle of sarcomere, the M line. The thick filaments are made from myosin II filaments and other proteins in a bipolar formation, which are attached to the Z lines using titin protein. They overlap with actin filaments. The cross bridge cycle helps myosin II walk along the actin molecule causing them to slide past each other and the sarcomere shortens. The thick filaments move towards the positive end of the thin actin filaments. Myosin heads only bind to actin in a short period of time so that the molecules can move fast past each other and muscles contraction can be fast, they are said to have little processivity [1].

However, in kinesin this type of cycle using lever arm doesn't occur. Instead it uses tiny motions of the binding site to regulate the binding and unbinding of motor domain to microtubule [1] [3]. The conformational changes occur in the neck region where there is a linker section that produces processive motion of the heads [1] [3]. This processive movement means that the kinesin dimer can hydrolyse ATP in many ATPase cycles to move along the microtubule without letting go [1] [5]. The first head is bound to ATP causing a change in linker region making it firmly attach to microtubule. This also swings the second head, with ADP bound, forward onto new binding site. The second head then releases ADP causing the interaction to strengthen. The first head hydrolyses ATP and releases inorganic phosphate, which weakens the binding. The binding site on second head becomes available for ATP to bind which causes the linker region to change shape and lock the head down firmly onto microtubule. These binding swings the first head forward onto new binding site [1] [3] [5]. Ref to fig 5.

This type of movement is used by cells for moving intracellular organelles such as lysosomes and vesicles from point of formation to cell periphery where its contents can be secreted by exocytosis [1] [3]. Microtubules are purposefully arranged in a cell so the pointed ends are in the centre and the barbed ends are towards the cell periphery [3]. Ref to fig 6. This is because kinesin moves from pointed end to barbed end of microtubule so organelles are transported from centre to the outside [3]. Long haul transport occurs in nerve terminals where synaptic vesicles and mitochondria are migrated in the axon of the nerve using kinesin as the motor protein and microtubules as the filament track [1] [3] [5]. The highly processive movement of kinesin makes sure that the molecules remains bound to the microtubule molecule, so when one head is finding a new binding site the other head will not let go until it does. This makes sure that the organelle it is moving doesn't dissociate before it reaches its destination [1] [3] [5].

Conclusion

Myosin II and Kinesin are very similar motor proteins in that there structures both consist of 2 heavy alpha helical polypeptide chains arranged in coiled coil, with 3 distinct domains [2]. These domains also help both motor proteins carry out similar sort of movements as they both uses motor domain for ATP and nucleotide binding site, neck domain for movement of motor domain, and the tail domain [2] [3]. They both use chemical energy, usually in form of ATP hydrolysis, to perform interactions with the actin and microtubule filaments, transducing the chemical energy into mechanical. ATP hydrolysis is associated with structural changes in the neck and head region of the two molecules [1].

The precise movement produced and the functions that they both carry out however are slightly different. Myosin II carries out the cross bridge cycle, using the head region as a lever arm to perform its power stokes. The movement isn't processive which helps the protein perform quicker movement as found in striated muscles [1] [2]. Kinesin uses processive movement of the head regions, where there are small movements at the binding site to bind with microtubule molecule. This movement is much slower as the heads mainly remain firmly connected during ATPase cycle, making sure the molecules doesn't dissociate away in the cytosol [1] [3].

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