The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
Motifs binding the TPR domain of kinesin light chain 1
Functional site description:
Kinesins are important microtubule motors for binding and anterograde transport of cellular cargo such as vesicles and organelles. The conventional kinesin 1 oligomer consists of a heavy chain dimer functioning as an ATP hydrolysing motor domain and two identical light chains (KLC) containing tetratricopeptide repeat (TPR) regions for binding cellular cargo. These TPRs form rod-like structures that mediate protein interactions by recognizing and binding a variety of cargo proteins such as caytaxin and calsyntenin, proteins involved in neuronal development and maturation. Since the KLC TPR is also recruited by viral envelope and bacterial associated proteins it is also important to the life cycle of invasive pathogens. A 'WD' motif has been shown to bind the KLC1 and KLC2 TPR and thereby mediate cargo transport. More recently a second class of KLC1 isoform-specific motif, termed 'Y-acidic’ has been identified in some adaptor proteins like JIP1 and TorsinA.

ELMs with same func. site: LIG_KLC1_WD_1  LIG_KLC1_Yacidic_2 
ELM Description:
The light chains (KLCs) of the heterotetrameric microtubule motor kinesin-1 can use their TPR domains to bind cargo proteins through a short peptide sequence named Y acidic motif. This motif is identified in a limited number of proteins that includes JIP1, TorsinA and SH2D6. The core region of the motif consists of a tyrosine residue within two semiconserved hydrophobic residues, flanked by acidic residues. The binding specificities of the Y-acidic and W-acidic motifs (LIG_KLC1_WD_1) are distinct and they use partially overlapping sites on the concave surface of KLC1 TPR for binding. The solved structures of JIP1 (6FUZ) and TorsinA (6FV0) in complex with KLC1 show that both use a common mode for KLC1 adapter binding (Pernigo,2018). The motifs bind in an extended conformation to the positively-charged inner surface of the TPR solenoid structure in a direction opposite to that of super-helical coiling accompanied by an open-to-closed transition of its solenoid structure. The conserved tyrosine (P0) within the Y-acidic core is stabilized by residues from a cavity located between TRP3 and TRP4. The main chain atoms of two hydrophobic residues at positions P-1 and P+1 make hydrogen bonds with two asparagine pairs (N386/N343 and N301/N344). The glutamate at position p+2 is stabilized by salt bridges with residues R266 and K340. The C-terminal motifs in JIP1 and Torsin A are so strongly conserved that they are of limited help in defining the range of Y-acidic motif preferences. The lower affinity SH2D6 motif shows more variability and was used to develop the pattern for ELM. In most species, SH2D6 proteins have more than one motif match, suggesting that they might make multiple cooperative interactions with the heterotetrameric motor complexes.
Pattern: [ED].{0,1}[IYVLMTF]Y[LIV][DE]
Pattern Probability: 0.0000204
Present in taxon: Metazoa
Interaction Domain:
TPR_7 (PF13176) Tetratricopeptide repeat (Stochiometry: 1 : 1)
o See 3 Instances for LIG_KLC1_Yacidic_2
o Abstract
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.
o 4 selected references:

o 5 GO-Terms:

o 3 Instances for LIG_KLC1_Yacidic_2
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q9ER39 Tor1a
328 332 VFSDKGCKTVFTKLDYYLDD TP 3 Mus musculus (House mouse)
707 711 QQFYKQFVEYTCPTEDIYLE TP 5 Homo sapiens (Human)
Q9D413 Sh2d6
103 108 MVTKKPDEDIYLECEPDPVP TP 1 Mus musculus (House mouse)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement