Amino-terminal acetylation of proteins in mammalian biology and disease

项目总结

PROJECT SUMMARY Although the scientific community has made substantial progress in elucidating the function of many genes, much remains unknown, particularly concerning the diversity introduced into proteins with co- and post- translational modifications. One such modification is amino-terminal acetylation (NTA), which is considerably understudied, with very few reports on the mammalian N-terminome. Protein acetylation occurs both at lysine residues within proteins (lysine acetylation or N-ε-acetylation) and at the N-terminus of proteins (Nt-acetylation or N--acetylation). Protein Nt-acetylation is among the most common modifications of eukaryotic proteins and is carried out by N-terminal acetyltransferases (NATs). The knockdown phenotypes of human NATs in cell culture suggest that protein NTA is an essential modification in human cells to maintain proliferation, but functional insights and mammalian in vivo models are lacking. Understanding of a general role for NTA remains elusive, and only a few examples in which NTA affects protein function, complex formation, activity, or stability are known. My laboratory discovered and characterized the first genetic disease coupled to N-terminal acetylation (NTA) of proteins, involving a missense mutation in the X-linked gene NAA10; we named this rare disease Ogden syndrome (OS) in honor of the hometown (Ogden, Utah), where the first family we identified with OS lived. The affected boys have a distinct combination of craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, cardiac anomalies, and cardiomegaly. We and others then found more than a dozen families with overlapping phenotypes with additional mutations in NAA10 in this pathway; we also reported recently that de novo mutations in NAA15, encoding a binding partner for NAA10, are involved in congenital heart defects and/or neurodevelopment. This finding is consistent with the range of cardiac anomalies and neurodevelopmental delays seen in OS (now more broadly known as NAA10-related disorders). As part of our long-term focus on the mechanistic dissection of NTA, over the next five years, we will focus on detailed phenotyping of humans with mutations in the pathway, alongside a systems-level study of unique mouse models, including conditional alleles, using histologic and functional approaches to provide the first mechanistic insights into the role of NTA in cardiac development and mammalian physiology. We will also continue our analysis of a newly identified enzyme in the pathway, which we propose compensates for and prevents embryonic lethality in humans and mouse models with mutations in NAA10. This R35 grant will enable the study of the molecular biology and pathophysiology associated with NAA10- and NAA15-related disorders and the NTA pathway, as part of a sustained effort to understand the role of NTA in mammalian biology. These studies will be a critical step toward revealing the role of NTA in human health and disease, as NTA has been linked to cancer progression and neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and Huntington’s diseases.