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• W3166202912 abstract "Beclin 1 (BECN1) is a key regulator of autophagy, a critical catabolic homeostasis pathway that involves the sequestration of cytoplasmic components by multilayered vesicles called autophagosomes, followed by lysosomal fusion and degradation. BECN1 is a core component of class III phosphatidylinositol-3-kinase complexes responsible for autophagosome nucleation. Without heterologous binding partners, BECN1 forms an antiparallel homodimer via its coiled-coil domain (CCD). However, the last 16 CCD residues, composing an “overlap helix” (OH), have been crystallized in two mutually exclusive states: either as part of the CCD or packed against the C-terminal β-α repeated, autophagy-specific domain (BARAD). Here, using circular dichroism (CD) spectroscopy, isothermal titration calorimetry (ITC), and small-angle X-ray scattering (SAXS), we show that in the homodimeric state, the OH transitions between these two different packing states, with the predominant state comprising the OH packed against the BARAD, contrary to expectations based on known BECN1 interactions with heterologous partners. We confirmed this observation by comparing the impact of mutating four residues that mediate packing of the OH against both the CCD and BARAD on structure and stability of the CCD, the OH+BARAD, and the two-domain CCD–BARAD. We also used cellular assays demonstrating that mutation of these OH-interface residues abrogates starvation-induced up-regulation of autophagy, but does not affect basal autophagy. Lastly, we have obtained crystals of the CCD–BARAD that we are optimizing for X-ray diffraction in order to obtain an atomic-resolution, three-dimensional structure of the homodimer. In summary, we have identified a BECN1 helical region that transitions between packing as part of either one of two conserved domains, i.e. the CCD or the BARAD. Our findings have important implications for the relative stability of autophagy-inactive and autophagy-active BECN1 complexes. Support or Funding Information This work was supported by NIH grants RO3 NS090939 and R15 GM122035 (S.S.) and R15 GM113227 (C.C.); a National Science Foundation grant MCB-1413525 (S.S.); a North Dakota State University Graduate School doctoral dissertation award for K.G.; and an ND EPSCoR doctoral dissertation award for K.G. Work performed at Bio-CAT was supported by NIH NIGMS 9P41 GM103622 and use of the Pilatus 3 1M detector funded by NIH NIGMS 1S10OD018090-01. This research used resources of the Advanced Photon Source, a U.S. DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. The authors also acknowledge the NDSU Core Biology Facility (funded by NIH grant P30 GM103332-01) for access to tissue culture facilities and the NDSU Advanced Imaging and Microscopy Core Laboratory for access to microscopy and imaging equipment. We also thank Dr. Pawel Borowicz for assistance with imaging and puncta quantification method development. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal." @default.
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• W3166202912 date "2018-04-01" @default.
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• W3166202912 title "Structural Transitions in Conserved, Ordered Beclin 1 Domains Essential to Regulating Autophagy" @default.
• W3166202912 doi "https://doi.org/10.1096/fasebj.2018.32.1_supplement.792.15" @default.
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