Myristoylation, an Ancient Protein Modification Mirroring Eukaryogenesis and Evolution

MYR is an essential protein modification found in all eukaryotes, with the catalysts involved validated as drug targets in a number of human diseases. New studies on MYR at the proteome scale have revealed novel MYR features, compartments, and targets, as well as roles in quality control, the immune system, cell motility, and mitochondrial components. Detailed target analysis reveals that myristoylated substrates mark all eukaryotic compartments, including those only arising in specific organisms or resulting from cellular differentiation. Less than ten N-myristoylated targets are conserved throughout evolution and are associated with the earliest events recapitulating eukaryogenesis, suggesting MYR accompanied eukaryotic evolution. New structural and biochemical data on N-myristoyltransferases illuminate novel catalytic mechanism and substrate specificity. N-myristoylation (MYR) is a crucial fatty acylation catalyzed by N-myristoyltransferases (NMTs) that is likely to have appeared over 2 billion years ago. Proteome-wide approaches have now delivered an exhaustive list of substrates undergoing MYR across approximately 2% of any proteome, with constituents, several unexpected, associated with different membrane compartments. A set of <10 proteins conserved in eukaryotes probably represents the original set of N-myristoylated targets, marking major changes occurring throughout eukaryogenesis. Recent findings have revealed unexpected mechanisms and reactivity, suggesting competition with other acylations that are likely to influence cellular homeostasis and the steady state of the modification landscape. Here, we review recent advances in NMT catalysis, substrate specificity, and MYR proteomics, and discuss concepts regarding MYR during evolution. N-myristoylation (MYR) is a crucial fatty acylation catalyzed by N-myristoyltransferases (NMTs) that is likely to have appeared over 2 billion years ago. Proteome-wide approaches have now delivered an exhaustive list of substrates undergoing MYR across approximately 2% of any proteome, with constituents, several unexpected, associated with different membrane compartments. A set of <10 proteins conserved in eukaryotes probably represents the original set of N-myristoylated targets, marking major changes occurring throughout eukaryogenesis. Recent findings have revealed unexpected mechanisms and reactivity, suggesting competition with other acylations that are likely to influence cellular homeostasis and the steady state of the modification landscape. Here, we review recent advances in NMT catalysis, substrate specificity, and MYR proteomics, and discuss concepts regarding MYR during evolution. a 2.5-MDa molecular machine controlling ubiquitin-dependent proteolysis in eukaryotes made of two (19S-regulatory and 20S-core proteolytic) complexes. small GTPases essential in eukaryotes that function in vesicular trafficking and actin remodeling. mechanism allowing degradation or recycling of cellular components by fusion to lysosomes. an event occurring while the nascent protein chain is not yet complete and still bound to the ribosome. specific sequence in a protein that directs its degradation via the 26S proteasome or autophagy. approximately 2-billion-year process by which eukaryotes evolved from an Archaeon. Last eukaryotic common ancestor (LACA) and first eukaryotic common ancestor (FECA) witnessed progressive emergence of endomembranes, nuclei, and organelles. early markers of eukaryogenesis and including DNA, RNA, and protein synthesis proteins but also endosomal sorting complex required for transport, small GTPases, cytoskeletal proteins, and ubiquitin signaling proteins. all life on Earth has evolved from common ancestors in an unbroken chain since its origin, approximately 3.8 billion years ago. a protoeukaryote with endomembranes (~2.4 billion years ago). a large enzyme superfamily that transfer acyl derivatives from acyl-CoA donors to a variety of acceptors. hydrolyze GTP into GDP, include small proteins like ARFs or large ones such as heterotrimeric G proteins, major molecular switches of signal transduction pathways located at the PM. an archaeon featuring ESPs such as cytoskeletal proteins and membrane trafficking systems. featuring fully differentiated internal structures (~1 billion years ago). enzymes cleaving the first methionine of approx. 60% proteins to unmask small residues such as glycines. cell surface proteins essential for vertebrate acquired immunity. maintains crista integrity and mitochondrial function. a saturated (i.e., without double bonds) 14 carbon fatty acid (C14:0). complete set of MYRed proteins in a proteome. catalytic subunit of N-α-acetyltransferase A (NatA), an NAA operating on small N-terminal residues such as glycine. a lipid acylation of proteins using MyrCoA as a myristate donor; makes amide bonds with free amino groups, usually from N-terminal glycines. refers to glycine MYR in large-scale analyses. the MYR catalyst, part of the GNAT family, uses MyrCoA as donor. a modification occurring on the N termini of proteins. Various complexes have been described, such as NatA and NatB, depending their substrate specificity. Involves 80% of proteins of multicellular eukaryotes. catalyzed by membrane enzymes, occurs anywhere on cysteine residues provided a membrane-binding motif (transmembrane helix/helices, lipid modification) brings the residue to the interface. protein derivative from one gene, may differ by one modification. the proteome steady-state homeostasis as guaranteed by a network of quality control components ensuring proteins integrity. non-receptor Src family of protein tyrosine kinases, nine members, none in plants.