Structural and functional analysis of the
            <scp>GABARAP</scp>
            interaction motif (
            <scp>GIM</scp>
            )

Rogov, Vladimir V.; Stolz, Alexandra; Ravichandran, Arvind; Rios-Szwed, Diana; Suzuki, Hisao; Kniss, Andreas; Löhr, Frank; Wakatsuki, Soichi; Dötsch, Volker; Đikić, Ivan; Dobson, Renwick C. J.; McEwan, David G.

doi:10.15252/embr.201847268

Cited by 25 publications

(31 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This raises an ongoing question as to how specificity within the system is achieved, particularly in mammalian systems that are complicated by the expression of six LC3/GABARAP isoforms. We, and others [13,43,44], have attempted to decipher the code that dictates whether a protein with a particular LIR sequence will preferentially interact with LC3 over GABARAP.…”

Section: Resultsmentioning

confidence: 99%

“…p-p70S6K (T389) was used as a marker for starved cells and total p70S6K as loading control. Interestingly, ATG2A and ATG2B do not conform to the recently identified GABARAP interaction motif consensus sequence (W/F-I/V-X-I/ V) [13] despite preferring GABARAP and GABARAP-L1 over LC3 in co-immunoprecipitation from cells (Figs EV1D, 1E and 2B and C). Surprisingly, both ATG2A and ATG2B can also interact with LC3A ( Fig EV1D); however, we have been unable to confirm an endogenous interaction.…”

mentioning

confidence: 85%

“…LC3/GABARAP proteins, once conjugated to PE, can localize to both the inner and outer autophagosomal membranes. This allows the ATG8s to interact with proteins containing an LC3 interaction region (LIR), linking the phagophore to the cargo or the phagophore/autophagosome to the cellular transport and fusion machinery [10][11][12][13]. The majority of LIR motifs contain a core W/Y/F-x-x-L/I/V motif.…”

Section: Introductionmentioning

confidence: 99%

“…The majority of LIR motifs contain a core W/Y/F-x-x-L/I/V motif. In addition, acidic and/or phosphorylatable serine/threonine residues N-and C-terminal of the core LIR sequence can contribute to the stabilization of LIR-ATG8 interactions [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A conserved ATG2‐GABARAP family interaction is critical for phagophore formation

et al. 2020

Self Cite

View full text Add to dashboard Cite

The intracellular trafficking pathway, macroautophagy, is a recycling and disposal service that can be upregulated during periods of stress to maintain cellular homeostasis. An essential phase is the elongation and closure of the phagophore to seal and isolate unwanted cargo prior to lysosomal degradation. Human ATG2A and ATG2B proteins, through their interaction with WIPI proteins, are thought to be key players during phagophore elongation and closure, but little mechanistic detail is known about their function. We have identified a highly conserved motif driving the interaction between human ATG2 and GABARAP proteins that is in close proximity to the ATG2‐WIPI4 interaction site. We show that the ATG2A‐GABARAP interaction mutants are unable to form and close phagophores resulting in blocked autophagy, similar to ATG2A/ATG2B double‐knockout cells. In contrast, the ATG2A‐WIPI4 interaction mutant fully restored phagophore formation and autophagy flux, similar to wild‐type ATG2A. Taken together, we provide new mechanistic insights into the requirements for ATG2 function at the phagophore and suggest that an ATG2‐GABARAP/GABARAP‐L1 interaction is essential for phagophore formation, whereas ATG2‐WIPI4 interaction is dispensable.

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A conserved ATG2‐GABARAP family interaction is critical for phagophore formation

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Proteins and entire organelles or their portions can be selectively delivered to AVs via receptor-mediated processes. Autophagy receptors harbour a LC3 or GABARAP interaction motif (LIR or GIM, respectively) that facilitates binding of the cargo to LC3 or GABARAP proteins, which decorate autophagosomal membranes [27,28]. A notable example of selective autophagy is ER-phagy.…”

Section: The 'Er-phagy' Pathwaymentioning

confidence: 99%

Emerging lysosomal pathways for quality control at the endoplasmic reticulum

2019

View full text Add to dashboard Cite

Protein misfolding occurring in the endoplasmic reticulum (ER) might eventually lead to aggregation and cellular distress, and is a primary pathogenic mechanism in multiple human disorders. Mammals have developed evolutionary‐conserved quality control mechanisms at the level of the ER. The best characterized is the ER‐associated degradation (ERAD) pathway, through which misfolded proteins translocate from the ER to the cytosol and are subsequently proteasomally degraded. However, increasing evidence indicates that additional quality control mechanisms apply for misfolded ER clients that are not eligible for ERAD. This review focuses on the alternative, ERAD‐independent, mechanisms of clearance of misfolded polypeptides from the ER. These processes, collectively referred to as ER‐to‐lysosome–associated degradation, involve ER‐phagy, microautophagy or vesicular transport. The identification of the underlying molecular mechanisms is particularly important for developing new therapeutic approaches for human diseases associated with protein aggregate formation.

show abstract

The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways

et al. 2021

Self Cite

View full text Add to dashboard Cite

The lysosome is a cellular signalling hub at the point of convergence of endocytic and autophagic pathways, where the contents are degraded and recycled. Pleckstrin homology domain‐containing family member 1 (PLEKHM1) acts as an adaptor to facilitate the fusion of endocytic and autophagic vesicles with the lysosome. However, it is unclear how PLEKHM1 function at the lysosome is controlled. Herein, we show that PLEKHM1 coprecipitates with, and is directly phosphorylated by, mTOR. Using a phosphospecific antibody against Ser432/S435 of PLEKHM1, we show that the same motif is a direct target for ERK2‐mediated phosphorylation in a growth factor‐dependent manner. This dual regulation of PLEKHM1 at a highly conserved region points to a convergence of both growth factor‐ and amino acid‐sensing pathways, placing PLEKHM1 at a critical juncture of cellular metabolism.

show abstract

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

Cited by 25 publications

References 17 publications

A conserved ATG2‐GABARAP family interaction is critical for phagophore formation

A conserved ATG2‐GABARAP family interaction is critical for phagophore formation

Emerging lysosomal pathways for quality control at the endoplasmic reticulum

The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways

Contact Info

Product

Resources

About