Structure of the Novel C-terminal Domain of Vacuolar Protein Sorting 30/Autophagy-related Protein 6 and Its Specific Role in Autophagy

Abstract

Background: Vps30/Atg6 is responsible for both autophagy and vacuolar protein sorting.Results: Structure of the Vps30 BARA domain was determined and its function was characterized.Conclusion: BARA domain has a unique fold and is specifically required for autophagy.Significance: This study will be a basis for elucidating the various functions of Vps30 homologs.

Structure-based Analyses Reveal Distinct Binding Sites for Atg2 and Phosphoinositides in Atg18

“…5). This kind of interdependence between two Atg proteins for PAS targeting is also observed for Atg6-Atg14 and Atg5-Atg16 complexes (38,39). However, the mechanisms underlying this interdependent targeting of Atg proteins to the PAS have yet to be elucidated.…”

AMPK regulates autophagy by phosphorylating BECN1 at threonine 388

“…21,[24][25][26] Although BECN1 phosphorylation has been reported in autophagy regulation, the effects of BARA domain phosphorylation are still not understood. 10 This study demonstrates that AMPK phosphorylates BECN1 at Thr388 in the BARA domain to induce autophagy.…”

“…Although the function of the BARA domain is not clear, structural analysis shows that the BARA domain of BECN1 is essential for autophagy and for targeting of the PtdIns3K to the site of phagophore formation. 10 Presumably, it may play a key role in promoting the formation of the PIK3C3-BECN1-ATG14 complex. Because Thr388 is located in repeat 3 of the BECN1 BARA domain it is possible that BECN1 Thr388 is important to the formation of the PIK3C3-BECN1 complex and nucleation of phagophores.…”

“…The N-terminal region of BECN1 is responsible for vacuolar protein sorting. 10 BECN1 is a component of the PtdIns3K complexes that participate in phagophore nucleation and elongation. 11 BECN1 recruits ATG14 or UVRAG to the PtdIns3K complexes to promote autophagy.…”

Structural biology of the macroautophagy machinery

“…This domain is essential to both autophagy and Beclin1's tumor suppressive function . The recent crystal structures of human Beclin1 ECD (residues 248-450) and yeast Atg6 ECD (319-540) have revealed additional roles for this domain (Huang et al, 2012;Noda et al, 2012). Human Beclin1 ECD consists of four α-helices and three anti-parallel β-sheets, arranged into three α/β repeats showing three fold symmetry.…”