Journal Article

DKFZ-2025-00952

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Biochemical investigation of LC3/GABARAP-ligand interaction as an important quality measure for LC3/GABARAP-targeting small molecules: addendum to the guidelines (4th edition).

Schwalm, M. P.DKFZ* ; Lenz, C. ; Saxena, K.DKFZ* ; Klionsky, D. J. ; Proschak, E. ; Knapp, S.DKFZ*

2025
Taylor & Francis Abingdon, Oxon

Abstract: Targeted protein degradation (TPD) represents a new therapeutic modality that allows the targeting of proteins that are considered undruggable by conventional small molecules. While TPD approaches via the ubiquitin-proteasome system are well established and validated, additional degradation pathways still require rigorous characterization. Here, we focus on macroautophagy/autophagy tethering compounds, a class of small molecules, designed to recruit cargo to LC3/GABARAP proteins for subsequent autophagosome-dependent degradation. We provide guidance for the biophysical and structural characterization of small molecule modulators for studying LC3/GABARAP-ligand interactions. In addition, we discuss potential limitations of autophagy-based TPD systems and emphasize the need for rigorous quality control in the development of LC3/GABARAP-targeting small molecules.Abbreviations: DSF: differential scanning fluorimetry; FP: fluorescence polarization; FRET: Förster/fluorescence resonance energy transfer; HTRF: homogeneous time-resolved fluorescence; ITC: isothermal titration calorimetry; LIR: LC3-interacting region; MGs: molecular glues; NMR: nuclear magnetic resonance; PROTACs: PROteolysis-TArgeting Chimeras; SPR: surface plasmon resonance; TPD: targeted protein degradation; TR-FRET: time-resolved Förster/fluorescence resonance energy transfer; UPS: ubiquitin-proteasome system.

Keyword(s): ATTECs ; AUTACs ; Atg8 ; GABARAP ; LC3

Note: ISSN 1554-8635 / 2025 Sep;21(9):2069-2073

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Frankfurt (FM01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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