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Structural and functional analysis of the GABARAP interaction motif (GIM)

Journal Article · · EMBO Reports
 [1];  [2];  [3];  [4];  [5];  [1];  [1];  [6];  [1];  [7];  [8];  [9]
  1. Goethe Univ., Frankfurt am Main (Germany)
  2. Goethe Univ. School of Medicine, Frankfurt (Main) (Germany)
  3. Univ. of Canterbury, Christchurch (New Zealand)
  4. Univ. of Dundee, Dundee (United Kingdom)
  5. Univ. of Canterbury, Christchurch (New Zealand); High Energy Accelerator Research Organization (KEK), Tsukuba Ibaraki (Japan)
  6. High Energy Accelerator Research Organization (KEK), Tsukuba Ibaraki (Japan); SLAC National Accelerator Lab., Menlo Park, CA (United States); Structural Biology (School of Medicine), Stanford, CA (United States)
  7. Goethe Univ. School of Medicine, Frankfurt (Main) (Germany); Goethe Univ., Frankfurt am Main (Germany)
  8. Univ. of Canterbury, Christchurch (New Zealand); Univ. of Melbourne, Parkville, VIC (Australia)
  9. Goethe Univ. School of Medicine, Frankfurt (Main) (Germany); Univ. of Dundee, Dundee (United Kingdom)
+ Show Author Affiliations

Through the canonical LC3 interaction motif (LIR), [W/F/Y]–X1–X2[I/L/V], protein complexes are recruited to autophagosomes to perform their functions as either autophagy adaptors or receptors. How these adaptors/receptors selectively interact with either LC3 or GABARAP families remains unclear. Herein, we determine the range of selectivity of 30 known core LIR motifs towards individual LC3s and GABARAPs. From these, we define a GABARAP Interaction Motif (GIM) sequence ([W/F]–[V/I]–X2–V) that the adaptor protein PLEKHM1 tightly conforms to. Using biophysical and structural approaches, we show that the PLEKHM1–LIR is indeed 11–fold more specific for GABARAP than LC3B. Selective mutation of the X1 and X2 positions either completely abolished the interaction with all LC3 and GABARAPs or increased PLEKHM1–GIM selectivity 20–fold towards LC3B. Finally, we show that conversion of p62/SQSTM1, FUNDC1 and FIP200 LIRs into our newly defined GIM, by introducing two valine residues, enhances their interaction with endogenous GABARAP over LC3B. In conclusion, the identification of a GABARAP–specific interaction motif will aid the identification and characterization of the expanding array of autophagy receptor and adaptor proteins and their in vivo functions.

Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1390293
Journal Information:
EMBO Reports, Journal Name: EMBO Reports Journal Issue: 8 Vol. 18; ISSN 1469-221X
Publisher:
European Molecular Biology OrganizationCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (40)

Emerging lysosomal pathways for quality control at the endoplasmic reticulum journal August 2019
Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP journal November 2018
ER-phagy and human diseases journal October 2019
LC3/GABARAPs drive ubiquitin-independent recruitment of Optineurin and NDP52 to amplify mitophagy journal January 2019
Autophagy regulates lipid metabolism through selective turnover of NCoR1 journal April 2019
Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins journal May 2019
Selective autophagy maintains centrosome integrity and accurate mitosis by turnover of centriolar satellites journal September 2019
A brief history of autophagy from cell biology to physiology and disease journal April 2018
Host–pathogen interactions and subversion of autophagy journal December 2017
A helical LC3-interacting region mediates the interaction between the retroviral restriction factor Trim5α and mammalian autophagy-related ATG8 proteins journal October 2018
Time-resolved FRET and NMR analyses reveal selective binding of peptides containing the LC3-interacting region to ATG8 family proteins journal July 2019
iLIR@viral: A web resource for LIR motif-containing proteins in viruses journal August 2017
Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs journal March 2019
Human LC3 and GABARAP subfamily members achieve functional specificity via specific structural modulations journal April 2019
An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5 journal April 2019
GABARAPs and LC3s have opposite roles in regulating ULK1 for autophagy induction journal June 2019
Human ubiquitin-like proteins as central coordinators in autophagy journal August 2018
Molecular interplay of autophagy and endocytosis in human health and diseases journal April 2019
ER‐phagy: shaping up and destressing the endoplasmic reticulum journal June 2019
Autophagy and autophagy-related proteins in cancer journal January 2020
ER-phagy at a glance journal September 2018
N-terminal β-strand underpins biochemical specialization of an ATG8 isoform journal July 2019
A selective ER ‐phagy exerts procollagen quality control via a Calnexin‐ FAM 134B complex journal November 2018
Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNARE s journal October 2019
A conserved ATG2‐GABARAP family interaction is critical for phagophore formation journal February 2020
Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs text January 2019
Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins. text January 2020
Dynamic Regulation of the 26S Proteasome: From Synthesis to Degradation journal June 2019
The Multifaceted Roles of Autophagy in Flavivirus-Host Interactions journal December 2018
Epstein–Barr Virus BALF0 and BALF1 Modulate Autophagy journal November 2019
A selective ER-phagy exerts procollagen quality control via a Calnexin-FAM134B complex text January 2019
Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs text January 2020
Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs text January 2019
Human LC3 and GABARAP subfamily members achieve functional specificity via specific structural modulations text January 2019
Human LC3 and GABARAP subfamily members achieve functional specificity via specific structural modulations text January 2020
An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5 text January 2019
An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5 text January 2019
GABARAPs and LC3s have opposite roles in regulating ULK1 for autophagy induction text January 2019
GABARAPs and LC3s have opposite roles in regulating ULK1 for autophagy induction text January 2019
A selective ER-phagy exerts procollagen quality control via a Calnexin-FAM134B complex. text January 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
Atg8
GABARAP
LC3
PLEKHM1
autophagy