LIG_KLC1_WD_1

Intracellular trafficking is strongly dependent on microtubule motor proteins such as kinesins or dyneins. The kinesin superfamily is comprised of ATPases that use energy to move macromolecules and organelles within the cell in the plus-end direction along microtubules. They can be classified into 15 subfamilies characterised by distinct structural modules and cellular functions (Verhey,2009, Hirokawa,2015). Kinesin 1, which is also known as conventional kinesin, is a heterotetramer consisting of two different subunits - the kinesin heavy chain (KHC) and the kinesin light chain (KLC). Thereby the KHCs provide the active motor function and the KLCs link the motor domain to the various cargo proteins for cargoes including vesicles, organelles, and mRNA. In particular the KLC TetratricoPeptide Repeats (TPR) that are well conserved in all four KLC paralogues, are key to this function since this region mediates the cargo recognition.
The TPR domain is found in many different proteins and with its structure of anti-parallel alpha-helices it provides an ideal interaction surface for other proteins. This structural domain, therefore, is important for a number of cellular processes involving protein interactions and the formation of multi-protein complexes. In the case of kinesin cargo binding, the TPRs recognise specific motifs that are essential for initiation of microtubule transport. An example for kinesin-dependent transport is the movement of vesicles containing neuronal peptides from the site of synthesis to more distant cellular regions and this is the basis for axonal growth as seen in calsyntenin (Konecna,2006) . Also caytaxin is transported by a similar mechanism and, if deficient, this causes clinical symptoms of dystonia and ataxia (Aoyama,2009). It has further been shown that lysosomes require kinesin-mediated microtubule transport for their intracellular distribution (Rosa-Ferreira,2011). Calsyntenin, caytaxin and other kinesin-1-associated cellular proteins have been found to possess similar 'WD' motifs responsible for binding to the KLC TPR module (Dodding,2011)
An alternative to the W-acidic motif, the “Y-acidic motif” was subsequently found in two proteins, JIP1 and TorsinA (Nguyen,2018; Pernigo,2018). The latter interact at a partially overlapped binding site relative to the W-acidic motif and therefore act independently. The c-Jun NH2-terminal kinase (JNK)-interacting protein 1 (JIP1) is involved in the anterograde transport of the amyloid precursor protein (APP), a key determinant in Alzheimer’s disease. TorsinA is a constitutively inactive AAA+ protein whose gene is linked to early-onset dystonia type 1 (DYT1) (Pernigo,2018). A third protein, the signalling adaptor SH2D6 has a Y-acidic motif that binds with lower affinity (Nguyen,2018).
Pathogens have evolved systems to hijack the Kinesin 1 system: Vaccinia virus integral membrane protein A36 utilises kinesin-mediated trafficking by mimicking the cellular WD TPR-binding motif for the transport of intracellular enveloped viruses towards the cell surface (Dodding,2011). Also SKIP, a cellular trafficking protein with a role in Golgi maintenance that is hijacked by the Salmonella major virulence protein SifA, possess a pair of WD motifs for KLC binding (Rosa-Ferreira,2011; Pernigo,2013). Understanding of the exact mechanisms of TPR:WD interactions in trafficking might provide insight or even intervention opportunities in pathological processes.