Abstract
Cyclin dependent kinase-5 (cdk5)/p35 is a neuronal kinase that regulates key axonal and synaptic functions but the mechanisms by which it is transported to these locations are unknown. Lemur tyrosine kinase-2 (LMTK2) is a binding partner for p35 and here we show that LMTK2 also interacts with kinesin-1 light chains (KLC1/2). Binding to KLC1/2 involves a C-terminal tryptophan/aspartate (WD) motif in LMTK2 and the tetratricopeptide repeat (TPR) domains in KLC1/2, and this interaction facilitates axonal transport of LMTK2. Thus, siRNA loss of KLC1 or mutation of the WD motif disrupts axonal transport of LMTK2. We also show that LMTK2 facilitates the formation of a complex containing KLC1 and p35 and that siRNA loss of LMTK2 disrupts axonal transport of both p35 and cdk5. Finally, we show that LMTK2 levels are reduced in Alzheimer’s disease brains. Damage to axonal transport and altered cdk5/p35 are pathogenic features of Alzheimer’s disease. Thus, LMTK2 binds to KLC1 to direct axonal transport of p35 and its loss may contribute to Alzheimer’s disease.
Highlights
Dynamic changes to protein phosphorylation underpin many aspects of neuronal function. p35 is a binding partner and activator subunit of the neuronal serinethreonine kinase cdk5 [7, 23, 43, 47]
Lemur tyrosine kinase-2 (LMTK2) binds to Kinesin-1 light chains (KLC) via a C-terminal WD motif We tested whether LMTK2 might bind to KLC1 and KLC2 in immunoprecipitation assays
LMTK2 bound to both KLC1 and KLC2 in these assays and the interaction was only detected in LMTK2 + KLC1/KLC2 co-transfected cells which demonstrates the specificity of the assays (Fig. 1a)
Summary
Dynamic changes to protein phosphorylation underpin many aspects of neuronal function. p35 is a binding partner and activator subunit of the neuronal serinethreonine kinase cdk5 [7, 23, 43, 47]. Despite the major roles that p35 plays within axons and synapses, the mechanisms by which it is transported into and through axons to these locations are unknown Understanding these mechanisms is essential for properly comprehending p35 and cdk function in neurons and its dysfunction in Alzheimer’s disease. LMTK2 is a member of the lemur family of kinases which are a structurally unique group of kinases that are anchored in the membrane by a membrane-spanning region located at their extreme N-termini and which contain an N-terminally located kinase domain with a long C-terminal “tail” [3, 17, 18, 46, 53, 56] As such, they have been named after lemurs, the long-tailed Madagascan primates. Originally predicted to be a dual-specificity serine-threonine/tyrosine kinase, several
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