Regulation of cotranslational N-acetyltransferases by NAC

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Newly synthesized proteins are cotranslationally processed by various ribosome-associated biogenesis factors that ensure proper maturation, folding, and transport of nascent polypeptides. For productive cotranslational processing of proteins, the timing at which a factor binds to ribosomes is very crucial. For example, in eukaryotes, many cytosolic substrates must first be processed by N-terminal modifying enzymes such as methionine aminopeptidases (METAPs) and N-acetyltransferases (NATs) before folding of the nascent chain is initiated by a folding chaperone such as RAC. How the nascent chain processing factors bind to the ribosome in a substrate-specific and temporally coordinated manner is poorly understood. In previous studies, we found that the ribosomal access of cotranslational factors that transport secretory proteins (SRP and Sec61) is tightly regulated by the nascent polypeptide-associated complex (NAC), a ubiquitous heterodimeric complex located at the exit of the ribosomal tunnel. Recently, we discovered that NAC also specifically recruits the methionine aminopeptidase METAP1 to ribosomes translating cytosolic substrates. These findings suggest that NAC also controls initial cotranslational biogenesis steps of cytosolic proteins performed by N-terminal modifying enzymes including NATs. The mechanism of how the five members of the NAT protein family specifically access nascent substrates and how they interact with NAC at the ribosomal tunnel exit is unknown. To better understand the ribosome interaction mechanisms of NATs we will (i) study the functional importance of NAC for N-terminal acetylation in vivo, and (ii) elucidating the ribosome binding mechanisms of NATs and their molecular interplay with NAC in vitro.