Multi-site-mediated entwining of the linear WIR-motif around WIPI β-propellers for autophagy

Ren, Jinqi; Liang, Rongrui; Wang, Wenjuan; Zhang, Dachuan; Liu, Yü; Feng, Wei

doi:10.1038/s41467-020-16523-y

Cited by 38 publications

(58 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Statistics of crystallographic data collection and structure refinement are provided in Supplementary Table 1. As expected on the basis of the Hsv2 (Baskaran et al, 2012;Krick et al, 2012;Watanabe et al, 2012) and WIPI3 (Ren et al, 2020) structures, WIPI2d folds into a seven blade b-propeller, with each blade containing four anti-parallel b-strands. The propeller is ~50 Å wide and ~30 Å tall (Fig.…”

Section: Structure Determination Of Wipi2d:atg16l1-w2irsupporting

confidence: 68%

“…The Val-and Pro-rich ATG2A sequence that binds to WIPI3 in an extended conformation (Ren et al, 2020), and presumably WIPI4, is completely different in character from the Leu-and Glurich helical W2IR of ATG16L1. We propose the term WIPI3/4 interacting region (W34IR) for the ATG2A binding motif to contrast it with the distinct W2IR of ATG16L1.…”

Section: Discussionmentioning

confidence: 96%

See 1 more Smart Citation

Structural Basis for Membrane Recruitment of ATG16L1 by WIPI2 in Autophagy

Strong

Chang

Boecker

et al. 2021

Preprint

View full text Add to dashboard Cite

Autophagy is a cellular process that degrades cytoplasmic cargo by engulfing it in a double membrane vesicle, known as the autophagosome, and delivering it to the lysosome. The ATG12-5-16L1 complex is responsible for conjugating members of the ubiquitin-like ATG8 protein family to phosphatidylethanolamine in the growing autophagosomal membrane, known as the phagophore. ATG12-5-16L1 is recruited to the phagophore by a subset of the phosphatidylinositol 3-phosphate-binding seven bladed beta-propeller WIPI proteins. We determined the crystal structure of WIPI2d in complex with the WIPI2 interacting region (W2IR) of ATG16L1 comprising residues 207-230 at 1.85 Angstrom resolution. The structure shows that the ATG16L1 W2IR adopts an alpha helical conformation and binds in an electropositive and hydrophobic groove between WIPI2 beta-propeller blades 2 and 3. Mutation of residues at the interface reduces or blocks the recruitment of ATG12-5-16L1 and the conjugation of the ATG8 protein LC3B to synthetic membranes. Interface mutants show a decrease in starvation-induced autophagy. Comparisons across the four human WIPIs suggest that WIPI1 and 2 belong to a W2IR-binding subclass responsible for localizing ATG12-5-16L1 and driving ATG8 lipidation, whilst WIPI3 and 4 belong to a second W34IR-binding subclass responsible for localizing ATG2, and so directing lipid supply to the nascent phagophore. The structure provides a framework for understanding the regulatory node connecting two central events in autophagy initiation, the action of the autophagic PI 3-kinase complex on the one hand, and ATG8 lipidation on the other.

show abstract

Section: Structure Determination Of Wipi2d:atg16l1-w2irsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 96%

Structural Basis for Membrane Recruitment of ATG16L1 by WIPI2 in Autophagy

Strong

Chang

Boecker

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The best characterized molecular function of WDR45 is promoting lipid transfer together with ATG2 proteins between adjacent membranes. This function at the phagophore-ER membrane contact sites is important for autophagy [34][35][36][37][38][39][40][41]101]. It cannot be excluded a priori that these proteins also participate in transferring lipids at other membrane contact sites and that a disruption caused by WDR45 mutations could contribute to the pathogenicity of WDR45-associated diseases.…”

Section: Discussionmentioning

confidence: 99%

WDR45, one gene associated with multiple neurodevelopmental disorders

Cong

Tijssen

et al. 2021

Autophagy

View full text Add to dashboard Cite

The WDR45 gene is localized on the X-chromosome and variants in this gene are linked to six different neurodegenerative disorders, i.e., ß-propeller protein associated neurodegeneration, Rett-like syndrome, intellectual disability, and epileptic encephalopathies including developmental and epileptic encephalopathy, early-onset epileptic encephalopathy and West syndrome and potentially also specific malignancies. WDR45/WIPI4 is a WD-repeat β-propeller protein that belongs to the WIPI (WD repeat domain, phosphoinositide interacting) family. The precise cellular function of WDR45 is still largely unknown, but deletions or conventional variants in WDR45 can lead to macroautophagy/autophagy defects, malfunctioning mitochondria, endoplasmic reticulum stress and unbalanced iron homeostasis, suggesting that this protein functions in one or more pathways regulating directly or indirectly those processes. As a result, the underlying cause of the WDR45-associated disorders remains unknown. In this review, we summarize the current knowledge about the cellular and physiological functions of WDR45 and highlight how genetic variants in its encoding gene may contribute to the pathophysiology of the associated diseases. In particular, we connect clinical manifestations of the disorders with their potential cellular origin of malfunctioning and critically discuss whether it is possible that one of the most prominent shared features, i.e., brain iron accumulation, is the primary cause for those disorders.

show abstract

“…Previous functional studies demonstrated that the four mammalian WIPI proteins can be classi ed into two sub-groups: the WIPI1/2 group and the WIPI3/4 group, which can speci cally recognize ATG16L1 and ATG2A/B, respectively [10][11][12]14 . The molecular mechanism governing the selective interaction of WIPI3/4 with ATG2 has been well elucidated by a recent elegant structural study 48 . In this study, we determined the WIPI2b/ATG16L1 complex structure, and uncovered the detailed binding mechanism as well as the key determinants for the speci c interaction between WIPI2b and ATG16L1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insights into the distinct functions of ATG16L1 in canonical autophagy and selective autophagy

Pan

Gong

Wang

et al. 2021

Preprint

View full text Add to dashboard Cite

Macroautophagy plays crucial roles in the regulation of cellular physiology, and requires de novo synthesis of double-membrane autophagosomes. The formation of autophagosomes entails the lipidation of ATG8 family proteins catalyzed by the ATG12 ~ ATG5-ATG16L1 complex, which is recruited to the pre-autophagosomal membrane through a direct interaction between ATG16L1 and WIPI2b. In addition, ATG16L1 can function as an adaptor to specifically recognize invading pathogens to mediate antibacterial selective autophagy, and the T300A polymorphism of ATG16L1 has been associated with the Crohn's disease, an inflammatory bowel disease mainly caused by the defect in antibacterial autophagy. However, the molecular mechanism governing the interaction of ATG16L1 with WIPI2b and the precise role of ATG16L1 in selective autophagy remain elusive. Here, we reported the atomic structure of the WIPI2b/ATG16L1 complex, and elucidated the mechanistic basis underpinning the recruitment of ATG16L1 by WIPI2b. Moreover, we discovered that the FIR motif of ATG16L1 not only can directly interact with RB1CC1 Claw domain, but also can selectively recognize mammalian ATG8 family proteins. We determined the high-resolution crystal structures of ATG16L1 FIR in complex with RB1CC1 Claw and GABARAPL1 respectively, and uncovered the molecular mechanism underlying the interactions of ATG16L1 with RB1CC1 and ATG8 family proteins. On this basis, we proposed the concept that ATG16L1 can be categorized as a potential autophagy receptor. In all, our findings provide novel mechanistic insights into the interactions of ATG16L1 with WIPI2b, RB1CC1 and ATG8 family proteins, and are valuable for further understanding the distinct functions of ATG16L1 in autophagy.

show abstract

Multi-site-mediated entwining of the linear WIR-motif around WIPI β-propellers for autophagy

Cited by 38 publications

References 36 publications

Structural Basis for Membrane Recruitment of ATG16L1 by WIPI2 in Autophagy

Structural Basis for Membrane Recruitment of ATG16L1 by WIPI2 in Autophagy

WDR45, one gene associated with multiple neurodevelopmental disorders

Mechanistic insights into the distinct functions of ATG16L1 in canonical autophagy and selective autophagy

Contact Info

Product

Resources

About