The significance of the 1-kinase/1-phosphatase activities of the PPIP5K family

Abstract

The inositol pyrophosphates (diphosphoinositol polyphosphates), which include 1-InsP₇, 5-InsP₇, and InsP₈, are highly 'energetic' signaling molecules that play important roles in many cellular processes, particularly with regards to phosphate and bioenergetic homeostasis. Two classes of kinases synthesize the PP-InsPs: IP6Ks and PPIP5Ks. The significance of the IP6Ks - and their 5-InsP₇ product - has been widely reported. However, relatively little is known about the biological significance of the PPIP5Ks. The purpose of this review is to provide an update on developments in our understanding of key features of the PPIP5Ks, which we believe strengthens the hypothesis that their catalytic activities serve important cellular functions. Central to this discussion is the recent discovery that the PPIP5K is a rare example of a single protein that catalyzes a kinase/phosphatase futile cycle.

Figure 1.. Inositol Pyrophosphate Turnover and the PPIP5Ks.

The schematic denotes the contributions to inositol pyrophosphate turnover of the 5-kinase activities of IP6Ks, the 1-kinase and 1-phosphatase activities of PPIP5Ks, and the DIPP phosphatases.

Figure 2. Domain graphic for PPIP5K1 and PPIP5K2

The figure depicts a domain graphic for human PPIP5K1 (BC057395.1) and human PPIP5K2 (XM_005271938). The so-called CPA (Contains Penta-Arginine) region in PPIP5K2 is rigorously conserved throughout metazoans; the eponymous pent-arginine is a functional nuclear localization sequence (Yong et al. 2015). However, transcripts containing this CPA domain (e.g., XM_005277536.1) are relatively poorly expressed in human cells (or at least those that we have examined), possibly as a consequence of rare, alternate splicing. In the figure, the amino acid residues defining each domain in PPIP5K1 are numbered as in a previous study, which also defined the intrinsically disordered domain (IDR) (Machkalyan et al. 2016). These boundaries were matched to those of the corresponding domains in PPIP5K2 by sequence alignments using Clustal Omega (http://www.ebi.ac.uk/Tools/msa/clustalo/). The aligned IDR boundaries in PPIP5K2 are consistent with those independently predicted from the PSIPRED Protein Sequence Analysis Workbench (http://bioinf.cs.ucl.ac.uk/psipred/).The % sequence identities across each of the three domains are also indicated.