How Kinesin-1 Utilize the Energy of Nucleotide: The Conformational Changes and Mechanochemical Coupling in the Unidirectional Motion of Kinesin-1

1. Introduction

Kinesin is a molecular walking motor protein inside cells. The size of kinesin is smaller than the other two members of motor proteins, myosin and dynein. The kinesin proteins can be divided into 14 subfamilies according to their structural and functional similarities (from kinesin-1 to kinesin-14) [1,2,3,4]. The kinesin-1 subfamily (also called conventional kinesin) is the founding member of the kinesin family [5,6] and mainly exists in the nerve axons to transport membranous organelles along microtubule lattice. Different from the kinesin-3 (monomer, but can also form a dimer [7]) and the kinesin-5 (tetramer) subfamily, the members of kinesin-1 form a dimer structure in vivo to “walk” toward the microtubule’s plus end. The entire structure of kinesin-1 can be mainly divided into three domains, i.e., the motor domain, the tail domain and the stalk domain (the motor domain and a part of stalk domain of kinesin-1 are shown in Figure 1). The motor domain (also called motor head), which contains the nucleotide-binding and microtubule-binding sites, is highly conserved among the kinesin family. The tail domain of kinesin-1 is used to bind with the “cargo”. Kinesin-1 proteins have different tail domains, which can bind the light chain to interact with different cargos [8]. The motor domain and the tail domain are connected by a single long α-helix, which is called the stalk domain. The two stalk domains of two kinesin-1 monomers coil together to form a coiled-coil structure and constitute a functional dimer. It is worthwhile to note that ~14 residues constitute the neck linker of kinesin-1, which connects the motor domain and the stalk domain. The conformational changes of the neck linker in different nucleotide-binding states are the key processes in the walking movement of kinesin-1 [9,10,11,12,13]. Because the motor domain locates in the N-terminal part of the protein, kinesin-1 belongs to the N-type kinesin. Kinesins with the motor domain located in the middle and the C-terminal part of the protein are the M-type and C-type, respectively. The walking directionality of kinesin varies with different locations of the motor domain. N-type kinesins (most members of the kinesin family) walk toward the plus end of the microtubule (some of the kinesin-5 proteins with N-terminal motor domain show bidirectional motility, as reviewed in Ref. [14]). In contrast, the C-type kinesin (mainly kinesin-14 subfamily [15]) walks toward the minus end of the microtubule. The M-type kinesin (mainly kinesin-13 subfamily) is relatively special because it takes one-dimensional diffusion toward the two ends of the microtubule [16,17,18,19].The kinesin-1 dimer walks along a single protofilament of the microtubule in a hand-over-hand manner. There are some noteworthy features of kinesin-1 walking movement: (1) Kinesin-1 can transform chemical energy of the adenosine triphosphate (ATP) binding and hydrolysis to mechanical energy of the walking along the microtubule with a cargo. (2) The chemical cycle and the mechanical cycle of kinesin-1 are highly coupled to ensure only one ATP molecule is consumed in one step [20,21]. The futile ATP hydrolysis rarely happens in kinesin-1 normal walking process. (3) The microtubule not only provides the track for the motility of kinesin-1 but also directly participates in the regulation of the kinesin-1 chemical cycle. The microtubule can catalyze the release of adenosine diphosphate (ADP), which is the product of ATP hydrolysis. In this way, the mechanochemical process of kinesin-1 is dramatically accelerated. The key process of energy transformation is from ATP entering the nucleotide-binding pocket to the docking movement of the neck linker, which pulls the other motor domain to the next binding site on the microtubule. How the conformational changes induced by the ATP binding can transmit to the neck linker region and finally drive the neck linker docking is an essential question in the walking mechanism of kinesin-1. In this paper, research on the conformational changes from the ATP binding to the neck liner docking and the coupling of mechanochemical cycle of kinesin-1 is reviewed.

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About the Author: Tung Chi