# Amino-terminal acetylation of proteins in mammalian biology and disease

> **NIH NIH R35** · INSTITUTE FOR BASIC RES IN DEV DISABIL · 2022 · $238,612

## Abstract

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- (or N-) 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
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
focus on the mechanistic dissection of NTA, we are undertaking detailed metabolic characterization of patient-
derived induced pluripotent stem cell lines. In this instrument supplement application, we are requesting
purchase of an Agilent Seahorse machine, which is the gold standard for reliable, accurate, and routine
measurements that can be applied to assess glycolytic rates, energy expenditure (e.g., cellular activation,
proliferation, differentiation), adenosine triphosphate production rate in real-time, substrate oxidation,
mitochondrial function, cell death, and general cellular homeostasis. This instrument will enable us to expand
our 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 d...

## Key facts

- **NIH application ID:** 10604927
- **Project number:** 3R35GM133408-04S1
- **Recipient organization:** INSTITUTE FOR BASIC RES IN DEV DISABIL
- **Principal Investigator:** GHOLSON LYON
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $238,612
- **Award type:** 3
- **Project period:** 2019-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10604927

## Citation

> US National Institutes of Health, RePORTER application 10604927, Amino-terminal acetylation of proteins in mammalian biology and disease (3R35GM133408-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10604927. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*