Rapidly Degraded Polypeptides in Protein Quality Control

Duke University, Durham NC

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The degradation of newly translated polypeptides is a poorly understood component of protein quality control. In eukaryotic cells, up to 30% of all nascent polypeptides are rapidly degraded with a half-life of ~10 minutes. Why do cells make so many polypeptides that are rapidly destroyed? Susceptibility to this rapid degradation does not depend on the usual, established half-life (t1/2) of a protein. Thus, a nascent protein molecule can either fold to yield a stable form (t1/2 = 1-2 days, on average) or be directed to the rapidly degraded polypeptide (RDP) pool (t1/2 = -10 minutes). Because RDPs derive from newly made polypeptides, we hypothesize that RDPs represent a critical intermediate in protein quality control. RDPs were first discovered in studies of antigen presentation, because they are the predominant source of peptides presented on major histocompatibility complex class I (MHC class I) molecules. Because MHC I- bound peptides derive primarily from RDPs, translation and MHC I presentation are tightly coupled. This coupling allows cytotoxic T lymphocytes to quickly detect when a virus has hijacked the cellular translation machinery. Therefore, we anticipate that understanding the biology of RDPs will lead to valuable insights into adaptive immunity and improve our ability to design vaccines that elicit optimal immune responses. RDPs are difficult to study because they are, by definition, unstable. We propose a novel approach to study RDPs directly using a reporter encoding an antigenic peptide. We will apply this reporter system to investigate the regulation of RDP production. Public Health Relevance: Our proposed research will explore the mechanisms that lead to the rapid destruction of newly made proteins. This research will facilitate improvements in vaccine design and potentially lead to new approaches for the treatment of genetic diseases. [unreadable] [unreadable] [unreadable]