Order-to-Disorder Transitions in BECN1 Regulate Autophagy

Journal Article · Wed Apr 01 04:00:00 EDT 2015 · The FASEB Journal (Online)

OSTI ID:1334448

Sinha, Sangita ^[1]; Mei, Yang ^[1]; Glover, Karen ^[1]; Su, Minfei ^[1]; Ramanathan, Arvind ^[2]; Colbert, Chris ^[1]

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1. North Dakota State Univ., Fargo, ND (United States). Dept. of Chemistry and Biochemistry
2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Health Data Sciences Inst.

Autophagy, an essential conserved, cell survival pathway in eukaryotes is responsible for degradation and recycling of unwanted, damaged or harmful cytoplasmic components. Our pathway-wide bioinformatics analysis shows that intrinsically disordered regions (IDRs) are the most common structural feature of autophagy proteins and these IDRs may be responsible for many regulatory interactions. BECN1 is a critical component of the autophagy nucleation complex. Aberrant or reduced autophagy, due to BECN1 defects or low levels is implicated in many diseases. Over 20 cellular or viral proteins appear to interact with BECN1 to modulate autophagy. We are also using a multi-faceted experimental approach encompassing bioinformatics, computational, structural, biophysical, biochemical, cell biology and molecular biology methods to understand the mechanism by which BECN1 mediates autophagy, and how partners bind to BECN1 to modulate autophagy. This work reveals a structural and functional dichotomy within the 450-residue human BECN1: residues 42-132 constitute a poorly conserved IDR that includes a BECN1 BH3 domain (BH3D) responsible for binding Bcl-2 proteins, while the highly-conserved C-terminal residues 133-450 comprise three conformationally-flexible domains: the helical domain (HD), the coiled-coil domain and the b-a-repeat in autophagy domain. Finally, our structural and biophysical results show that the BH3D and HD undergo binding-associated disorder-to-structure transitions and have identified residues important for regulating autophagy.

• Research Organization: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
• Sponsoring Organization: USDOE; National Institutes of Health (NIH); National Science Foundation (NSF)
• DOE Contract Number: AC05-00OR22725
• OSTI ID: 1334448
• Journal Information: The FASEB Journal (Online), Journal Name: The FASEB Journal (Online) Journal Issue: 1-Supplement Vol. 29; ISSN 1530-6860
• Publisher: Federation of American Societies for Experimental Biology
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES