title: Intrinsically disordered regions in autophagy proteins.
abstract: Autophagy is an essential eukaryotic pathway required for cellular homeostasis. Numerous key autophagy effectors and regulators have been identified, but the mechanism by which they carry out their function in autophagy is not fully understood. Our rigorous bioinformatic analysis shows that the majority of key human autophagy proteins include intrinsically disordered regions (IDRs), which are sequences lacking stable secondary and tertiary structure; suggesting that IDRs play an important, yet hitherto uninvestigated, role in autophagy. Available crystal structures corroborate the absence of structure in some of these predicted IDRs. Regions of orthologs equivalent to the IDRs predicted in the human autophagy proteins are poorly conserved, indicating that these regions may have diverse functions in different homologs. We also show that IDRs predicted in human proteins contain several regions predicted to facilitate protein-protein interactions, and delineate the network of proteins that interact with each predicted IDR-containing autophagy protein, suggesting that many of these interactions may involve IDRs. Lastly, we experimentally show that a BCL2 homology 3 domain (BH3D), within the key autophagy effector BECN1 is an IDR. This BH3D undergoes a dramatic conformational change from coil to α-helix upon binding to BCL2s, with the C-terminal half of this BH3D constituting a binding motif, which serves to anchor the interaction of the BH3D to BCL2s. The information presented here will help inform future in-depth investigations of the biological role and mechanism of IDRs in autophagy proteins.
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota, 58108-6050.
authors.forename: Yang
authors.initials: Y
authors.lastname: Mei
authors.forename: Minfei
authors.initials: M
authors.lastname: Su
authors.forename: Gaurav
authors.initials: G
authors.lastname: Soni
authors.forename: Saeed
authors.initials: S
authors.lastname: Salem
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Colbert
authors.forename: Sangita C
authors.initials: SC
authors.lastname: Sinha
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D064267:Intrinsically Disordered Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2
keywords: BCL2; BECN1; BH3 domain; autophagy; natively unstructured proteins; protein interactions; sequence analysis