The Molecular Basis for Post and Co-Translational N-Terminal Acetylation / Robert S Magin.

Format:

Book

Thesis/Dissertation

Author/Creator:

Magin, Robert S., author.

Contributor:

Marmorstein, Ronen, 1962- degree supervisor.

Duyne, Gregory D. Van, degree committee member.

Speicher, David W., degree committee member.

Petersson, E. James, degree committee member.

Kashina, A., degree committee member.

University of Pennsylvania. Biochemistry and Molecular Biophysics, degree granting institution.

Language:

English

Subjects (All):

Biochemistry.

Biochemistry and Molecular Biophysics--Penn dissertations.

Penn dissertations--Biochemistry and Molecular Biophysics.

Local Subjects:

Biochemistry.

Biochemistry and Molecular Biophysics--Penn dissertations.

Penn dissertations--Biochemistry and Molecular Biophysics.

Genre:

Academic theses.

Physical Description:

1 online resource (183 pages)

Contained In:

Dissertation Abstracts International 79-01B(E).

Place of Publication:

[Philadelphia, Pennsylvania]: University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2017.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

N-terminal acetylation is among the most common protein modifications in eukaryotic cells, where up to 90% of proteins carry this mark. Over the last decade, significant progress has been made in elucidating the function of N-terminal acetylation for a number of diverse systems. The enzymes responsible for this modification are the N-terminal acetyltransferases (NATs). The NATs are a group of conserved enzymes in eukaryotes, which can be broadly classified into two groups. The major NATs, NatA-NatC, are promiscuous and responsible for acetylating the majority of N-termini in the cell, and have hundreds to thousands of protein substrates. Recently, it has been suggested that they also may target lysine residues. These NATs largely act co-translationally. They interact with the ribosome near the exit tunnel and acetylate the nascent protein chain as it is being translated. The other NATs, NatD-NatF, are more specialized in their substrate specificity and localization patterns.

There is a large amount of structural information on the molecular basis of NAT activity. These studies have revealed how the NATs are specific for N-termini, and how binding partners affect their activity. However, the structural characteristics of the specialized NATs remain unknown, the full substrate scope of NATs remains to be determined, and how the NATs interact with the ribosome is largely unexplored, despite the importance of this modification in a co-translational context. Therefore, to address these gaps in knowledge, we determined the crystal structures of NatD and NatF with their substrate peptides bound, and by carrying out biochemical and enzymological assays, we revealed the molecular basis for their unique specificity and localization. We also showed that there is no difference in lysine acetylation of substrate proteins with or without NatA, suggesting that reported substrates are acetylated chemically rather than enzymatically. Finally, we determined regions on the NatA complex that promote interaction with the ribosome. This dissertation provides a framework for understanding the molecular basis of the specialized NATs, and how NATs interact with the ribosome for co-translational protein acetylation. These studies have implications in developing inhibitors for the specialized NATs, and in understanding co-translational events in general.

Notes:

Source: Dissertation Abstracts International, Volume: 79-01(E), Section: B.

Advisors: Ronen Marmorstein; Committee members: Anna Kashina; E. James Petersson; David W. Speicher; Gregory D. Van Duyne.

Department: Biochemistry and Molecular Biophysics.

Ph.D. University of Pennsylvania 2017.

Local Notes:

School code: 0175

ISBN:

9780355183474

Access Restriction:

Restricted for use by site license.