The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
'WD' motif binding TPR of kinesin light chain
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 -ike structures that mediate protein interactions by recognising and binding a variety of cargo proteins such as caytaxin and calsyntenin both being 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. It has been found in different cellular as well as viral proteins.
ELM Description:
The 'WD' motif is found in many cellular cargo proteins and is able to bind to the TPR region of the KLCs from kinesin 1. Hereby proteins such as calsyntenin, caytaxin, BNIP members and Gadkin recruit the KLC TPR to mediate active transport of molecules and vesicles in the plus-end direction along the microtubules. The motif consists of a WD or WE core often surrounded by other acidic residues. In most cases the motif also includes an L or other hydrophobic residue at two positions, one prior to the W and the other 5 or 6 residues after. The binding groove of TPR stabilises the binding motif with salt bridges and hydrogen bonds. It provides a leucine-rich pocket binding the W as well as a hydrophobic pocket holding the first L residue of the motif as shown in the crystal structure of KLC2 TPR with a peptide of SifA-kinesin interacting protein (SKIP or PKHM2; 3ZFW, Pernigo,2013). Most often, the motif is located toward C- or N-terminal regions of the cargo proteins. The motif has been associated with KLC1 and KLC2 but since the binding pocket is well-conserved it is likely to also bind other KLCs. Very often the 'WD' motif appears in pairs (bipartite) usually separated by less than 100 amino acids, suggesting cooperative function. However experimental evidence suggests that one motif can be sufficient for KLC binding. The consensus of the different 'WD' motifs could be summarised in the expression: ϕ[-]W[DE] [^+].{3,4}ϕ

Besides its cellular functions, the WD motif is also involved in bacterial pathogenesis mechanisms as in the targeted host protein SKIP and is also found in various viral proteins, such as A36 and F12 in vaccinia virus. Pathogens use the motif in order to 'hijack' cellular transport mechanisms and regulate movement of bacterial vacuoles or entire viruses within the cell.
Pattern: [LMTAFSRI][^KRG]W[DE].{3,5}[LIVMFPA]
Pattern Probability: 0.0003538
Present in taxons: Eukaryota Poxviridae
Interaction Domain:
TPR (SM00028) Tetratricopeptide repeats. (Stochiometry: 1 : 1)
o See 22 Instances for LIG_KLC1_WD_1
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 all with distinct structure and cellular functions (19851335, 25724902). 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, 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). In adddition, pathogens have evolved systems to hijack this mechanism: 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 8 selected references:

o 7 GO-Terms:

o 22 Instances for LIG_KLC1_WD_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
O14576 DYNC1I1
DC1I1_HUMAN
124 133 PLTRTLQWDTDPSVLQLQSD TP 1 Homo sapiens (Human)
O14576 DYNC1I1
DC1I1_HUMAN
81 88 VQPLHFLTWDTCYFHYLVPT TP 1 Homo sapiens (Human)
Q63HQ0 AP1AR
AP1AR_HUMAN
258 267 DDSNGLEWENDFVSAEMDDN TP 3 Homo sapiens (Human)
1 
Q63HQ0 AP1AR
AP1AR_HUMAN
208 216 STSLDLEWEDEEGMNRMLPM TP 1 Homo sapiens (Human)
Q8WUY3 PRUNE2
PRUN2_HUMAN
1136 1145 DMDNDLDWDDCSGGAAIPSD TP 1 Homo sapiens (Human)
Q7Z465 BNIPL
BNIPL_HUMAN
141 150 DSGHEFEWEDELPRAEGLGT TP 1 Homo sapiens (Human)
Q12982 BNIP2
BNIP2_HUMAN
95 104 ENSNEFEWEDDLPKPKTTEV TP 4 Homo sapiens (Human)
1 
Q8WXH0 SYNE2
SYNE2_HUMAN
6417 6425 VDSIPLEWDHTGDVGGSSSH TP 2 Homo sapiens (Human)
1 
Q1M168 Atcay
ATCAY_RAT
116 125 GNGNELEWEDDTPVATAKNM TP 3 Rattus norvegicus (Norway rat)
1 
Q8BHE3 Atcay
ATCAY_MOUSE
116 125 GNGNELEWEDDTPVATAKNM TP 4 Mus musculus (House mouse)
1 
Q86WG3 ATCAY
ATCAY_HUMAN
116 125 GNGNELEWEDDTPVATAKNM TP 1 Homo sapiens (Human)
1 
Q9EPL2 Clstn1
CSTN1_MOUSE
970 977 PGDGQNATRQLEWDDSTLSY TP 3 Mus musculus (House mouse)
2 
Q9EPL2 Clstn1
CSTN1_MOUSE
901 910 GKENEMDWDDSALTITVNPM TP 3 Mus musculus (House mouse)
2 
O94985 CLSTN1
CSTN1_HUMAN
972 979 DPQNATRQQQLEWDDSTLSY TP 4 Homo sapiens (Human)
1 
O94985 CLSTN1
CSTN1_HUMAN
901 910 GKENEMDWDDSALTITVNPM TP 3 Homo sapiens (Human)
1 
Q8IWE5 PLEKHM2
PKHM2_HUMAN
234 241 VPSVPSTDWEDGDLTDTVSG TP 8 Homo sapiens (Human)
2 
Q8IWE5 PLEKHM2
PKHM2_HUMAN
205 214 VTSTNLEWDDSAIAPSSEDY TP 9 Homo sapiens (Human)
2 
Q80HX6 VACWR051
F12_VACCW
534 543 VELGALQWDDNIPELKHGLL TP 2 Vaccinia virus WR
1 
A9J0X2 CVA167
A9J0X2_VACCA
95 104 SFAGSLIWDNESNVMAPSTE TP 2 Vaccinia virus Ankara
A9J0X2 CVA167
A9J0X2_VACCA
62 71 STDSESDWEDHCSAMEQNND TP 2 Vaccinia virus Ankara
P68619 VACWR159
A36_VACCW
95 104 SFAGSLIWDNESNVMAPSTE TP 4 Vaccinia virus WR
2 
P68619 VACWR159
A36_VACCW
62 71 STDSESDWEDHCSAMEQNND TP 2 Vaccinia virus WR
1 
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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