Abstract
T-complex testis expressed protein 1 domain containing 4 (TCTEX1D4) contains the canonical phosphoprotein phosphatase 1 (PPP1) binding motif, composed by the amino acid sequence RVSF. We identified and validated the binding of TCTEX1D4 to PPP1 and demonstrated that indeed this protein is a novel PPP1 interacting protein. Analyses of twenty-one mammalian species available in public databases and seven Lagomorpha sequences obtained in this work showed that the PPP1 binding motif 90RVSF93 is present in all of them and is flanked by a palindromic sequence, PLGS, except in three species of pikas (Ochotona princeps, O. dauurica and O. pusilla). Furthermore, for the Ochotona species an extra glycosylation site, motif 96NLS98, and the loss of the palindromic sequence were observed. Comparison with other lagomorphs suggests that this event happened before the Ochotona radiation. The dN/dS for the sequence region comprising the PPP1 binding motif and the flanking palindrome highly supports the hypothesis that for Ochotona species this region has been evolving under positive selection. In addition, mutational screening shows that the ability of pikas TCTEX1D4 to bind to PPP1 is maintained, although the PPP1 binding motif is disrupted, and the N- and C-terminal surrounding residues are also abrogated. These observations suggest pika as an ideal model to study novel PPP1 complexes regulatory mechanisms.
Highlights
Phosphoprotein phosphatase 1 (PPP1), one of the major eukaryotic serine/threonine protein phosphatases, has exquisite specificities in vivo, both in terms of substrates and cellular localization
We have demonstrated that TCTEX1D4 and PPP1C colocalize in the microtubule organizing center and in microtubules having a probable role in the cytoplasmic transport of the cell [22]
TCTEX1D4 has already been described as a new phosphoprotein phosphatase 1 (PPP1) interacting protein [22]
Summary
Phosphoprotein phosphatase 1 (PPP1), one of the major eukaryotic serine/threonine protein phosphatases, has exquisite specificities in vivo, both in terms of substrates and cellular localization. More than 200 interacting proteins have been identified, most of them having the consensus PPP1 binding motif (RVxF), that binds to the catalytic subunit of PPP1 (PPP1C), determining its targeting and specifying cellular location and function [3,4]. The RVxF motif is present in about 70% of all PPP1 interacting proteins [3]. This motif is usually surrounded by basic residues in the N-terminal and by acidic residues in the. The initial binding of this motif to PPP1C is essential to bring the PPP1 interacting proteins into its proximity, allowing for secondary interactions that strength holoenzyme binding, determining substrate specificity, enzyme activity and PPP1 isoform selectivity [9]. Several novel PPP1 interacting proteins have been identified, through a yeast two-hybrid system, using PPP1 as bait [10,11,12,13,14]
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