Conformational Flexibility Enables the Function of a BECN1 Region Essential for Starvation-Mediated Autophagy

Mei, Yang; Ramanathan, Arvind; Glover, Karen; Stanley, Christopher B.; Sanishvili, Ruslan; Chakravarthy, Srinivas; Yang, Zhongyu; Colbert, Christopher L.; Sinha, Sangita C.

doi:10.1021/acs.biochem.5b01264

Conformational Flexibility Enables the Function of a BECN1 Region Essential for Starvation-Mediated Autophagy

Journal Article · Thu Mar 03 00:00:00 EST 2016 · Biochemistry

DOI:https://doi.org/10.1021/acs.biochem.5b01264· OSTI ID:1424488

Mei, Yang ^[1]; ^[2]; Glover, Karen ^[1]; ^[3]; Sanishvili, Ruslan ^[4]; Chakravarthy, Srinivas ^[5]; Yang, Zhongyu ^[1]; Colbert, Christopher L. ^[1]; Sinha, Sangita C. ^[1]

North Dakota State Univ., Fargo, ND (United States). Department of Chemistry and Biochemistry
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Health Data Sciences Institute, Computational Science and Engineering Division
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biology and Soft Matter Division
Argonne National Lab. (ANL), Argonne, IL (United States). GMCA@APS, X-ray Science Division, Advanced Photon Source
Bio-CAT, Advanced Photon Source, Argonne, IL (United States)

BECN1 is essential for autophagy, a critical eukaryotic cellular homeostasis pathway. Here in this study, we delineate a highly conserved BECN1 domain located between previously characterized BH3 and coiled-coil domains and elucidate its structure and role in autophagy. The 2.0 Å sulfur-single-wavelength anomalous dispersion X-ray crystal structure of this domain demonstrates that its N-terminal half is unstructured while its C-terminal half is helical; hence, we name it the flexible helical domain (FHD). Circular dichroism spectroscopy, double electron–electron resonance–electron paramagnetic resonance, and small-angle X-ray scattering (SAXS) analyses confirm that the FHD is partially disordered, even in the context of adjacent BECN1 domains. Molecular dynamic simulations fitted to SAXS data indicate that the FHD transiently samples more helical conformations. FHD helicity increases in 2,2,2-trifluoroethanol, suggesting it may become more helical upon binding. Finally, cellular studies show that conserved FHD residues are required for starvation-induced autophagy. Thus, the FHD likely undergoes a binding-associated disorder-to-helix transition, and conserved residues critical for this interaction are essential for starvation-induced autophagy.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357; AC05-00OR22725

OSTI ID:: 1424488

Alternate ID(s):: OSTI ID: 1389814
OSTI ID: 1391662

Journal Information:: Biochemistry, Journal Name: Biochemistry Journal Issue: 13 Vol. 55; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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