6hyo

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Structure of ULK1 LIR motif bound to GABARAP

Structural highlights

6hyo is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.07Å
Ligands:EDO, GOL, PEG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GBRAP_HUMAN May play a role in intracellular transport of GABA(A) receptors and its interaction with the cytoskeleton. Involved in apoptosis. Involved in autophagy (By similarity).[1] ULK1_HUMAN Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK and also acts as a regulator of AMPK by mediating phosphorylation of AMPK subunits PRKAA1, PRKAB2 and PRKAG1, leading to negatively regulate AMPK activity. May phosphorylate ATG13/KIAA0652 and RPTOR; however such data need additional evidences. Plays a role early in neuronal differentiation and is required for granule cell axon formation.[2] [3] [4]

Publication Abstract from PubMed

Autophagy is an essential recycling and quality control pathway. Mammalian ATG8 proteins drive autophagosome formation and selective removal of protein aggregates and organelles by recruiting autophagy receptors and adaptors that contain a LC3-interacting region (LIR) motif. LIR motifs can be highly selective for ATG8 subfamily proteins (LC3s/GABARAPs), however the molecular determinants regulating these selective interactions remain elusive. Here we show that residues within the core LIR motif and adjacent C-terminal region as well as ATG8 subfamily-specific residues in the LIR docking site are critical for binding of receptors and adaptors to GABARAPs. Moreover, rendering GABARAP more LC3B-like impairs autophagy receptor degradation. Modulating LIR binding specificity of the centriolar satellite protein PCM1, implicated in autophagy and centrosomal function, alters its dynamics in cells. Our data provides new mechanistic insight into how selective binding of LIR motifs to GABARAPs is achieved, and elucidate the overlapping and distinct functions of ATG8 subfamily proteins.

Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins.,Wirth M, Zhang W, Razi M, Nyoni L, Joshi D, O'Reilly N, Johansen T, Tooze SA, Mouilleron S Nat Commun. 2019 May 3;10(1):2055. doi: 10.1038/s41467-019-10059-6. PMID:31053714[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
13 reviews cite this structure
The Overcrowded Crossroads: Mitochondria, Alpha-Synuclein, and the Endo-Lysosomal System Interaction in Parkinson's Disease.
Lin et al. (2019)
12 more
43 other articles
No citations found

See Also

References

  1. ↑ Lee JH, Rho SB, Chun T. GABAA receptor-associated protein (GABARAP) induces apoptosis by interacting with DEAD (Asp-Glu-Ala-Asp/His) box polypeptide 47 (DDX 47). Biotechnol Lett. 2005 May;27(9):623-8. PMID:15977068 doi:http://dx.doi.org/10.1007/s10529-005-3628-2
  2. ↑ Chan EY, Longatti A, McKnight NC, Tooze SA. Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol Cell Biol. 2009 Jan;29(1):157-71. doi: 10.1128/MCB.01082-08. Epub 2008 Oct, 20. PMID:18936157 doi:http://dx.doi.org/10.1128/MCB.01082-08
  3. ↑ Loffler AS, Alers S, Dieterle AM, Keppeler H, Franz-Wachtel M, Kundu M, Campbell DG, Wesselborg S, Alessi DR, Stork B. Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy. 2011 Jul;7(7):696-706. Epub 2011 Jul 1. PMID:21460634
  4. ↑ Jung CH, Seo M, Otto NM, Kim DH. ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy. 2011 Oct;7(10):1212-21. doi: 10.4161/auto.7.10.16660. Epub 2011 Oct 1. PMID:21795849 doi:http://dx.doi.org/10.4161/auto.7.10.16660
  5. ↑ Wirth M, Zhang W, Razi M, Nyoni L, Joshi D, O'Reilly N, Johansen T, Tooze SA, Mouilleron S. Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins. Nat Commun. 2019 May 3;10(1):2055. doi: 10.1038/s41467-019-10059-6. PMID:31053714 doi:http://dx.doi.org/10.1038/s41467-019-10059-6

Contents


PDB ID 6hyo

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OCA

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