Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination

Dae Gyu Kim; Minkyoung Kim; Ja il Goo; Jiwon Kong; Dipesh S. Harmalkar; Qili Lu; Aneesh Sivaraman; Hossam Nada; Sreenivasulu Godesi; Hwayoung Lee; Mo Eun Song; Eunjoo Song; Kang Hyun Han; Woojin Kim; Pilhan Kim; Won Jun Choi; Chang Hoon Lee; Sunkyung Lee; Yongseok Choi; Sunghoon Kim; Kyeong Lee

doi:10.1016/j.chembiol.2024.08.004

Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination

Dae Gyu Kim, Minkyoung Kim, Ja il Goo, Jiwon Kong, Dipesh S. Harmalkar, Qili Lu, Aneesh Sivaraman, Hossam Nada, Sreenivasulu Godesi, Hwayoung Lee, Mo Eun Song, Eunjoo Song, Kang Hyun Han, Woojin Kim, Pilhan Kim, Won Jun Choi, Chang Hoon Lee, Sunkyung Lee, Yongseok Choi, Sunghoon KimKyeong Lee

Research output: Contribution to journal › Article › peer-review

Abstract

AIMP2-DX2 (hereafter DX2) is an oncogenic variant of aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) that mediates tumorigenic interactions with various factors involved in cancer. Reducing the levels of DX2 can effectively inhibit tumorigenesis. We previously reported that DX2 can be degraded through Siah1-mediated ubiquitination. In this study, we identified a compound, SDL01, which enhanced the interaction between DX2 and Siah1, thereby facilitating the ubiquitin-dependent degradation of DX2. SDL01 was found to bind to the pocket surrounding the N-terminal flexible region and GST domain of DX2, causing a conformational change that stabilized its interaction with Siah1. Our findings demonstrate that protein-protein interactions (PPIs) can be modulated through chemically induced conformational changes.

Original language	English
Pages (from-to)	1958-1968.e8
Journal	Cell Chemical Biology
Volume	31
Issue number	11
DOIs	https://doi.org/10.1016/j.chembiol.2024.08.004
State	Published - 21 Nov 2024

Keywords

AIMP2-DX2
Siah1
allosteric modulation
and molecular docking
small molecule
ubiquitination

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2024.08.004

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Kim, D. G., Kim, M., Goo, J. I., Kong, J., Harmalkar, D. S., Lu, Q., Sivaraman, A., Nada, H., Godesi, S., Lee, H., Song, M. E., Song, E., Han, K. H., Kim, W., Kim, P., Choi, W. J., Lee, C. H., Lee, S., Choi, Y., ... Lee, K. (2024). Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination. Cell Chemical Biology, 31(11), 1958-1968.e8. https://doi.org/10.1016/j.chembiol.2024.08.004

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title = "Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination",

abstract = "AIMP2-DX2 (hereafter DX2) is an oncogenic variant of aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) that mediates tumorigenic interactions with various factors involved in cancer. Reducing the levels of DX2 can effectively inhibit tumorigenesis. We previously reported that DX2 can be degraded through Siah1-mediated ubiquitination. In this study, we identified a compound, SDL01, which enhanced the interaction between DX2 and Siah1, thereby facilitating the ubiquitin-dependent degradation of DX2. SDL01 was found to bind to the pocket surrounding the N-terminal flexible region and GST domain of DX2, causing a conformational change that stabilized its interaction with Siah1. Our findings demonstrate that protein-protein interactions (PPIs) can be modulated through chemically induced conformational changes.",

keywords = "AIMP2-DX2, Siah1, allosteric modulation, and molecular docking, small molecule, ubiquitination",

author = "Kim, {Dae Gyu} and Minkyoung Kim and Goo, {Ja il} and Jiwon Kong and Harmalkar, {Dipesh S.} and Qili Lu and Aneesh Sivaraman and Hossam Nada and Sreenivasulu Godesi and Hwayoung Lee and Song, {Mo Eun} and Eunjoo Song and Han, {Kang Hyun} and Woojin Kim and Pilhan Kim and Choi, {Won Jun} and Lee, {Chang Hoon} and Sunkyung Lee and Yongseok Choi and Sunghoon Kim and Kyeong Lee",

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year = "2024",

month = nov,

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doi = "10.1016/j.chembiol.2024.08.004",

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Kim, DG, Kim, M, Goo, JI, Kong, J, Harmalkar, DS, Lu, Q, Sivaraman, A , Nada, H, Godesi, S, Lee, H, Song, ME, Song, E, Han, KH, Kim, W, Kim, P, Choi, WJ, Lee, CH, Lee, S, Choi, Y, Kim, S & Lee, K 2024, 'Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination', Cell Chemical Biology, vol. 31, no. 11, pp. 1958-1968.e8. https://doi.org/10.1016/j.chembiol.2024.08.004

TY - JOUR

T1 - Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination

AU - Kim, Dae Gyu

AU - Kim, Minkyoung

AU - Goo, Ja il

AU - Kong, Jiwon

AU - Harmalkar, Dipesh S.

AU - Lu, Qili

AU - Sivaraman, Aneesh

AU - Nada, Hossam

AU - Godesi, Sreenivasulu

AU - Lee, Hwayoung

AU - Song, Mo Eun

AU - Song, Eunjoo

AU - Han, Kang Hyun

AU - Kim, Woojin

AU - Kim, Pilhan

AU - Choi, Won Jun

AU - Lee, Chang Hoon

AU - Lee, Sunkyung

AU - Choi, Yongseok

AU - Kim, Sunghoon

AU - Lee, Kyeong

PY - 2024/11/21

Y1 - 2024/11/21

N2 - AIMP2-DX2 (hereafter DX2) is an oncogenic variant of aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) that mediates tumorigenic interactions with various factors involved in cancer. Reducing the levels of DX2 can effectively inhibit tumorigenesis. We previously reported that DX2 can be degraded through Siah1-mediated ubiquitination. In this study, we identified a compound, SDL01, which enhanced the interaction between DX2 and Siah1, thereby facilitating the ubiquitin-dependent degradation of DX2. SDL01 was found to bind to the pocket surrounding the N-terminal flexible region and GST domain of DX2, causing a conformational change that stabilized its interaction with Siah1. Our findings demonstrate that protein-protein interactions (PPIs) can be modulated through chemically induced conformational changes.

AB - AIMP2-DX2 (hereafter DX2) is an oncogenic variant of aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) that mediates tumorigenic interactions with various factors involved in cancer. Reducing the levels of DX2 can effectively inhibit tumorigenesis. We previously reported that DX2 can be degraded through Siah1-mediated ubiquitination. In this study, we identified a compound, SDL01, which enhanced the interaction between DX2 and Siah1, thereby facilitating the ubiquitin-dependent degradation of DX2. SDL01 was found to bind to the pocket surrounding the N-terminal flexible region and GST domain of DX2, causing a conformational change that stabilized its interaction with Siah1. Our findings demonstrate that protein-protein interactions (PPIs) can be modulated through chemically induced conformational changes.

KW - AIMP2-DX2

KW - Siah1

KW - allosteric modulation

KW - and molecular docking

KW - small molecule

KW - ubiquitination

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U2 - 10.1016/j.chembiol.2024.08.004

DO - 10.1016/j.chembiol.2024.08.004

M3 - Article

C2 - 39260366

AN - SCOPUS:85207763467

SN - 2451-9456

VL - 31

SP - 1958-1968.e8

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 11

ER -

Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination

Abstract

Keywords

UN SDGs

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