Protein pyrophosphorylation: moving forward

Abstract

Genetic ablation of inositol pyrophosphate synthesis has established the fundamental importance of this class of molecules to the eukaryote cell. These studies, however, must be complemented by cell biology and biochemical approaches to appreciate the signalling involved in the processes regulated by inositol pyrophosphates. A recent study by Chanduri et al. published in the Biochemical Journal, by integrating multiple experimental approaches, demonstrated that inositol pyrophosphates regulate intracellular vesicular movement. In particular, the vesicular transport along the microtubule that is driven by the motor protein complex dynein. Importantly, one subunit of this cellular motor, dynein 1 intermediate chain 2, undergoes serine pyrophosphorylation, a post-translational modification driven by inositol pyrophosphates. The pyrophosphorylation status of this dynein intermediate chain regulates its interaction with dynactin, which recruits the motor to vesicles. This mechanistically might explain how inositol pyrophosphates control intracellular membrane trafficking. By dissecting the serine pyrophosphorylation process, this work increases our awareness of this modification, underappreciated by the scientific literature but probably not by the eukaryotic cell.

Structural and biochemical characterization of Siw14: A protein-tyrosine phosphatase fold that metabolizes inositol pyrophosphates

“…[1][2][3][4]. The highly electronegative and energetic properties of the PP-InsPs enable them to regulate protein functionality through both electrostatic interactions (1) and protein pyrophosphorylation (5). A number of biological effects have been attributed to the PP-InsPs, but most evidence favors a primary role in the regulation of metabolic circuitry (3,6,7).…”

Unambiguous Identification of Serine and Threonine Pyrophosphorylation Using Neutral-Loss-Triggered Electron-Transfer/Higher-Energy Collision Dissociation

“…Embedded within polyacidic stretches, this modification occurs on phosphorylated serine residues and is mediated by the inositol pyrophosphate messengers (PP-InsPs). − While a broad range of phenotypes have been linked to PP-InsPs, including insulin secretion, ribosome biogenesis in yeast, cancer cell migration, and blood clotting in mammals, − the role of protein pyrophosphorylation in regulating these diverse processes has not been elucidated. In fact, protein pyrophosphorylation remains a controversial topic of debate, − because the characterization of protein pyrophosphorylation has exclusively relied on in vitro labeling strategies. While these in vitro studies have led to the identification of a handful of yeast and mammalian pyrophosphorylation substrates, ,, direct molecular evidence for the presence of pyrophosphorylated proteins in vivo has not been presented to date.…”

Inositol polyphosphates and target of rapamycin kinase signalling govern photosystem II protein phosphorylation and photosynthetic function under light stress in Chlamydomonas

“…InsP 7 is a phosphate donor for different nucleolar proteins in yeast (NSR1 and SRP40) and mammals (Nopp140 and TCOF1) (Saiardi, 2004, 2012b, 2016; Bhandari et al ., 2007). The InsP 7 ‐derived phosphate is thought to be attached to a pre‐existing phosphorylation (β‐pyrophosphorylation), which may provide a unique mode of signalling to proteins.…”