Deubiquitinase USP19 extends the residual enzymatic activity of phenylalanine hydroxylase variants.
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| Abstract |
Phenylalanine hydroxylase (PAH) is a key enzyme in mammals that maintains the phenylalanine (Phe) concentration at an appropriate physiological level. Some genetic mutations in the PAH gene lead to destabilization of the PAH enzyme, leading to phenylketonuria (PKU). Destabilized PAH variants can have a certain amount of residual enzymatic activity that is sufficient for metabolism of Phe. However, accelerated degradation of those variants can lead to insufficient amounts of cellular PAH protein. The optimal protein level of PAH in cells is regulated by a balancing act between E3 ligases and deubiquitinating enzymes (DUBs). In this work, we analyzed the protein expression and stability of two PKU-linked PAH protein variants, R241C and R243Q, prevalent in the Asian population. We found that the tested PAH variants were highly ubiquitinated and thus targeted for rapid protein degradation. We demonstrated that USP19, a DUB that interacts with both PAH variants, plays a regulatory role by extending their half-lives. The deubiquitinating activity of USP19 prevents protein degradation and increases the abundance of both PAH protein variants. Thus, our study reveals a novel mechanism by which deubiquitinating activity of USP19 extends the residual enzymatic activity of PAH variants.
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| Authors | Neha Sarodaya, Apoorvi Tyagi, Hyun-Jin Kim, Ju-Seop Kang, Vijai Singh, Seok-Ho Hong, Woo Jin Kim, Kye-Seong Kim, Suresh Ramakrishna |
| Journal | Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 14243 (08 20 2022) ISSN: 2045-2322 [Electronic] England |
| PMID | 35987969 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2022. The Author(s). |
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