Protein acetylation is the most ancient and common form of posttranslational modification, and the vast majority of the human proteome is acetylated. Protein acetylation is mediated by protein lysine acetyltransferases (KATs), which are grouped into Histone ATs (HATs) and non-histone ATs, and protein N-terminal ATs (NATs). In mammalian cells, KATs acetylate thousands of proteins, spanning a wide class spectrum, including transcription factors, kinases, ubiquitinligases, ribosomal proteins and metabolic enzymes, and mediating a broad range of cellular activities, including cell cycle control, DNA damage check-points, cytoskeleton organization, endocytosis and metabolism. The posttranslational and cotranslational process of N-terminal acetylation by NATs occurs on ~85% of human proteins and is also involved in numerous biological processes including cellular apoptosis, enzyme regulation, protein localization, rDNA transcriptional regulation and protein degradation. Aberrant AT activities have also been associated with several diseases including solid and haematological cancers, rare genetic disorders, and metabolic and neurodegenerative disorders, thus implicating ATs as attractive drug targets for therapy. Despite the importance of ATs, mechanistic information is largely limited to the isolated catalytic AT domains, and the critical role played by AT cofactor and auxiliary proteins in mediating AT-regulated cellular pathways are largely unknown. In addition, potent, selective and cell permeable AT inhibitors as molecular probes for AT-mediated pathways and as lead molecules for therapy are generally not available. The overall goal of this proposal is to understand the molecular mechanisms of protein acetylation by HATs, non-histone KATs and NATs, with a particular focus on addressing the following unresolved and important questions and goals in the field: (A) How are HATs regulated by cofactor proteins for substrate-specific acetylation? (B) What are the unique AT properties of non-histone KATs? (C) How do auxiliary proteins and ribosome association contribute to NAT function? (D) Can we leverage mechanistic and structural information to develop potent and selective protein AT inhibitors?

Public Health Relevance

Protein acetylation is the most ancient and common form of posttranslational modification and the vast majority of human proteins are acetylated. Protein acetylation is mediated by protein acetyltransferase (AT) enzymes, which mediate many biological processes and often have altered function in human diseases. Despite the importance of ATs, mechanistic information is very limited and small molecule AT inhibitors that for therapy are not available. The overall goal of this proposal is to understand the molecular mechanisms of protein acetylation by ATs and to develop novel small molecule AT inhibitors as molecular probes and lead molecules for therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
3R35GM118090-04S1
Application #
9879364
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Barski, Oleg
Project Start
2016-07-01
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biochemistry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Gottlieb, Leah; Marmorstein, Ronen (2018) Structure of Human NatA and Its Regulation by the Huntingtin Interacting Protein HYPK. Structure 26:925-935.e8
Arnesen, Thomas; Marmorstein, Ronen; Dominguez, Roberto (2018) Actin's N-terminal acetyltransferase uncovered. Cytoskeleton (Hoboken) 75:318-322
Han, Joseph; Lachance, Catherine; Ricketts, M Daniel et al. (2018) The scaffolding protein JADE1 physically links the acetyltransferase subunit HBO1 with its histone H3-H4 substrate. J Biol Chem 293:4498-4509
Goris, Marianne; Magin, Robert S; Foyn, Håvard et al. (2018) Structural determinants and cellular environment define processed actin as the sole substrate of the N-terminal acetyltransferase NAA80. Proc Natl Acad Sci U S A 115:4405-4410
Ricketts, M Daniel; Marmorstein, Ronen (2017) A Molecular Prospective for HIRA Complex Assembly and H3.3-Specific Histone Chaperone Function. J Mol Biol 429:1924-1933
Simithy, Johayra; Sidoli, Simone; Yuan, Zuo-Fei et al. (2017) Characterization of histone acylations links chromatin modifications with metabolism. Nat Commun 8:1141
Magin, Robert S; Deng, Sunbin; Zhang, Haibo et al. (2017) Probing the interaction between NatA and the ribosome for co-translational protein acetylation. PLoS One 12:e0186278
McCullough, Cheryl E; Marmorstein, Ronen (2016) Molecular Basis for Histone Acetyltransferase Regulation by Binding Partners, Associated Domains, and Autoacetylation. ACS Chem Biol 11:632-42
Magin, Robert S; March, Zachary M; Marmorstein, Ronen (2016) The N-terminal Acetyltransferase Naa10/ARD1 Does Not Acetylate Lysine Residues. J Biol Chem 291:5270-7
Støve, Svein Isungset; Magin, Robert S; Foyn, Håvard et al. (2016) Crystal Structure of the Golgi-Associated Human N?-Acetyltransferase 60 Reveals the Molecular Determinants for Substrate-Specific Acetylation. Structure 24:1044-56

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