Roles of polyamines in translation

Abstract

Polyamines are organic polycations that bind to a variety of cellular molecules, including nucleic acids. Within cells, polyamines contribute to both the efficiency and fidelity of protein synthesis. In addition to directly acting on the translation apparatus to stimulate protein synthesis, the polyamine spermidine serves as a precursor for the essential post-translational modification of the eukaryotic translation factor 5A (eIF5A), which is required for synthesis of proteins containing problematic amino acid sequence motifs, including polyproline tracts, and for termination of translation. The impact of polyamines on translation is highlighted by autoregulation of the translation of mRNAs encoding key metabolic and regulatory proteins in the polyamine biosynthesis pathway, including S-adenosylmethionine decarboxylase (AdoMetDC), antizyme (OAZ), and antizyme inhibitor 1 (AZIN1). Here, we highlight the roles of polyamines in general translation and also in the translational regulation of polyamine biosynthesis.Because of their cationic properties, polyamines bind to negatively charged molecules in cells. Nucleic acids, including both DNA and RNA, are prominent binding sites for polyamines with nearly 90% of the spermidine in Escherichia coli cells bound to RNA (1). A substantial fraction (ϳ15%) of the polyamines in E. coli are stably associated with ribosomes (2). Polyamines stimulate general protein synthesis and also impact the fidelity of translation. The importance of polyamines to translation is highlighted by the mRNA-specific translational control mechanisms that link polyamine levels to the synthesis of key polyamine biosynthetic enzymes and their regulators. In this Minireview, we will highlight the roles of polyamines in general translation and in the translational regulation of polyamine biosynthesis. In honor of Herb Tabor, we will also highlight his contributions to this area of polyamine research.3 The abbreviations used are: A,

Mechanism of ribosome stalling during translation of a poly(A) tail

“…The PTC also contained two regions of unaccounted density that we have provisionally assigned as spermidine molecules. This assignment is plausible because spermidine is an abundant (~1-3 mM) cytosolic polyamine, fits the observed density, and is known to bind ribosomes at hundreds of sites 50 . Whether these putative spermidine molecules directly contribute to ribosome stalling or represent incidental interactions captured in our structure is currently unknown.…”

“…Two regions of unaccounted density near the PTC were fitted with spermidine molecules (ligand code SPD). We cannot be certain these densities represent spermidine, but it seems plausible because spermidine is an abundant cytosolic polyamine required for translation 51,52 , fits the observed density, and is well established to bind ribosomes in hundreds of sites 50 . The overall model was adjusted manually in Coot to conform with the density using suitably blurred maps (with B-factors between 0 and -200), saved in mmCIF/PDBx format and real space-refined using phenix.real_space_refine 70 .…”

“…Whether these putative spermidine molecules directly contribute to ribosome stalling or represent incidental interactions captured in our structure is currently unknown. The role of polyamines in any specific step of translation has been challenging to investigate because changes in polyamine levels potently impact multiple aspects of ribosome function in vitro and in cells [50][51][52] .…”

Introduction to the Thematic Minireview Series: Sixty plus years of polyamine research

“…The abilities of polyamines to influence protein synthesis at both the general and specific levels are elegantly described in the Minireview by Dever and Ivanov (22). Polyamine content can affect initiation, elongation, and termination in a variety of ways.…”

Polyamine-controlled proliferation and protein biosynthesis are independent determinants of hair follicle stem cell fate

“…One important determinant of translation rates is the availability of the natural 76 polyamines putrescine, spermidine, and spermine. These polycations are essential for 77 cell growth and can bind to a variety of negatively charged cellular molecules, including 78 nucleic acids (Dever & Ivanov, 2018). Polyamine homeostasis is critical to cell survival 79 and is achieved by coordinated regulation at different levels of their synthesis, 80 degradation, uptake and excretion (Wallace et al, 2003).…”