biostudies-literaturePernigo SBiotechnology and Biological Sciences Research Councile38362https://www.ebi.ac.uk/biostudies/studies/S-EPMC6214655biostudies-literatureUnknown7The light chains (KLCs) of the heterotetrameric microtubule motor kinesin-1, that bind to cargo adaptor proteins and regulate its activity, have a capacity to recognize short peptides via their tetratricopeptide repeat domains (KLC^TPR). Here, using X-ray crystallography, we show how kinesin-1 recognizes a novel class of adaptor motifs that we call 'Y-acidic' (tyrosine flanked by acidic residues), in a KLC-isoform-specific manner. Binding specificities of Y-acidic motifs (present in JIP1 and in TorsinA) to KLC1^TPR are distinct from those utilized for the recognition of W-acidic motifs, found in adaptors, that are KLC-isoform non-selective. However, a partial overlap on their receptor-binding sites implies that adaptors relying on Y-acidic and W-acidic motifs must act ieLifeStructural basis for isoform-specific kinesin-1 recognition of Y-acidic cargo adaptors.PMC6214655BB/S000917/1BB/S000828/1BB/L006774/1Bui SDodding MPPolitis ASteiner RAHansen KYip YYChegkazi MSTreacy CGlorani GPernigo SfalseStructural basis for isoform-specific kinesin-1 recognition of Y-acidic cargo adaptors.The light chains (KLCs) of the heterotetrameric microtubule motor kinesin-1, that bind to cargo adaptor proteins and regulate its activity, have a capacity to recognize short peptides via their tetratricopeptide repeat domains (KLC^TPR). Here, using X-ray crystallography, we show how kinesin-1 recognizes a novel class of adaptor motifs that we call 'Y-acidic' (tyrosine flanked by acidic residues), in a KLC-isoform-specific manner. Binding specificities of Y-acidic motifs (present in JIP1 and in TorsinA) to KLC1^TPR are distinct from those utilized for the recognition of W-acidic motifs, found in adaptors, that are KLC-isoform non-selective. However, a partial overlap on their receptor-binding sites implies that adaptors relying on Y-acidic and W-acidic motifs must act i2018-01-01T00:00:00Z2018 Oct2026-05-03T02:57:26.188Z2019-03-27T00:06:32ZS-EPMC62146553032055310.7554/eLife.38362