Delineation of critical amino acids in activation function 1 of progesterone receptor for recruitment of transcription coregulators
The activation functions AF1 and AF2 of nuclear receptors mediate the recruitment of coregulators in gene regulation. AF1 is mapped to the highly variable and intrinsically unstructured N terminal domain and AF2 lies in the conserved ligand binding domain. The unstructured nature of AF1 offers struc...
| Main Authors: | , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2020
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/143287 |
| _version_ | 1811691940535599104 |
|---|---|
| author | Woo, Amanda Rui En Sze, Siu Kwan Chung, Hwa Hwa Lin, Valerie Chun Ling |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Woo, Amanda Rui En Sze, Siu Kwan Chung, Hwa Hwa Lin, Valerie Chun Ling |
| author_sort | Woo, Amanda Rui En |
| collection | NTU |
| description | The activation functions AF1 and AF2 of nuclear receptors mediate the recruitment of coregulators in gene regulation. AF1 is mapped to the highly variable and intrinsically unstructured N terminal domain and AF2 lies in the conserved ligand binding domain. The unstructured nature of AF1 offers structural plasticity and hence functional versatility in gene regulation. However, little is known about the key functional residues of AF1 that mediates its interaction with coregulators. This study focuses on the progesterone receptor (PR) and reports the identification of K464, K481 and R492 (KKR) as the key functional residues of PR AF1. The KKR are monomethylated and function cooperatively. The combined mutations of KKR to QQQ render PR isoform B (PRB) hyperactive, whereas KKR to FFF mutations abolishes as much as 80% of PR activity. Furthermore, the hyperactive QQQ mutation rescues the loss of PR activity due to E911A mutation in AF2. The study also finds that the magnitudes of the mutational effect differ in different cell types as a result of differential effects on the functional interaction with coregulators. Furthermore, KKR provides the interface for AF1 to physically interact with p300 and SRC-1, and with AF2 at E911. Intriguingly, the inactive FFF mutant interacts strikingly stronger with both SRC-1 and AF2 than wt PRB. We propose a tripartite model to describe the dynamic interactions between AF1, AF2 and SRC-1 with KKR of AF1 and E911 of AF2 as the interface. An overly stable interaction would hamper the dynamics of disassembly of the receptor complex. |
| first_indexed | 2024-10-01T06:27:52Z |
| format | Journal Article |
| id | ntu-10356/143287 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:27:52Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | ntu-10356/1432872023-02-28T17:07:57Z Delineation of critical amino acids in activation function 1 of progesterone receptor for recruitment of transcription coregulators Woo, Amanda Rui En Sze, Siu Kwan Chung, Hwa Hwa Lin, Valerie Chun Ling School of Biological Sciences Science::Biological sciences Positively Charged Residues Progesterone Receptor The activation functions AF1 and AF2 of nuclear receptors mediate the recruitment of coregulators in gene regulation. AF1 is mapped to the highly variable and intrinsically unstructured N terminal domain and AF2 lies in the conserved ligand binding domain. The unstructured nature of AF1 offers structural plasticity and hence functional versatility in gene regulation. However, little is known about the key functional residues of AF1 that mediates its interaction with coregulators. This study focuses on the progesterone receptor (PR) and reports the identification of K464, K481 and R492 (KKR) as the key functional residues of PR AF1. The KKR are monomethylated and function cooperatively. The combined mutations of KKR to QQQ render PR isoform B (PRB) hyperactive, whereas KKR to FFF mutations abolishes as much as 80% of PR activity. Furthermore, the hyperactive QQQ mutation rescues the loss of PR activity due to E911A mutation in AF2. The study also finds that the magnitudes of the mutational effect differ in different cell types as a result of differential effects on the functional interaction with coregulators. Furthermore, KKR provides the interface for AF1 to physically interact with p300 and SRC-1, and with AF2 at E911. Intriguingly, the inactive FFF mutant interacts strikingly stronger with both SRC-1 and AF2 than wt PRB. We propose a tripartite model to describe the dynamic interactions between AF1, AF2 and SRC-1 with KKR of AF1 and E911 of AF2 as the interface. An overly stable interaction would hamper the dynamics of disassembly of the receptor complex. Ministry of Education (MOE) Nanyang Technological University Accepted version This work is supported by Ministry of Education of Singapore, Academic Research Fund Tier 2, MOE2014-T2-2-125. We thank Dr. Or Yu Zuan and Mr. Lim Chew Leng for their technical assistance (Nanyang Technological University, Singapore). 2020-08-19T04:21:59Z 2020-08-19T04:21:59Z 2019 Journal Article Woo, A. R. E., Sze, S. K., Chung, H. H., & Lin, V. C. L. (2019). Delineation of critical amino acids in activation function 1 of progesterone receptor for recruitment of transcription coregulators. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1862(4), 522-533. doi:10.1016/j.bbagrm.2019.01.004 1874-9399 https://hdl.handle.net/10356/143287 10.1016/j.bbagrm.2019.01.004 30716532 2-s2.0-85062099577 4 1862 522 533 en Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms © 2019 Elsevier B.V. All rights reserved. This paper was published in Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms and is made available with permission of Elsevier B.V. application/pdf |
| spellingShingle | Science::Biological sciences Positively Charged Residues Progesterone Receptor Woo, Amanda Rui En Sze, Siu Kwan Chung, Hwa Hwa Lin, Valerie Chun Ling Delineation of critical amino acids in activation function 1 of progesterone receptor for recruitment of transcription coregulators |
| title | Delineation of critical amino acids in activation function 1 of progesterone receptor for recruitment of transcription coregulators |
| title_full | Delineation of critical amino acids in activation function 1 of progesterone receptor for recruitment of transcription coregulators |
| title_fullStr | Delineation of critical amino acids in activation function 1 of progesterone receptor for recruitment of transcription coregulators |
| title_full_unstemmed | Delineation of critical amino acids in activation function 1 of progesterone receptor for recruitment of transcription coregulators |
| title_short | Delineation of critical amino acids in activation function 1 of progesterone receptor for recruitment of transcription coregulators |
| title_sort | delineation of critical amino acids in activation function 1 of progesterone receptor for recruitment of transcription coregulators |
| topic | Science::Biological sciences Positively Charged Residues Progesterone Receptor |
| url | https://hdl.handle.net/10356/143287 |
| work_keys_str_mv | AT wooamandaruien delineationofcriticalaminoacidsinactivationfunction1ofprogesteronereceptorforrecruitmentoftranscriptioncoregulators AT szesiukwan delineationofcriticalaminoacidsinactivationfunction1ofprogesteronereceptorforrecruitmentoftranscriptioncoregulators AT chunghwahwa delineationofcriticalaminoacidsinactivationfunction1ofprogesteronereceptorforrecruitmentoftranscriptioncoregulators AT linvaleriechunling delineationofcriticalaminoacidsinactivationfunction1ofprogesteronereceptorforrecruitmentoftranscriptioncoregulators |