title: BECN2 interacts with ATG14 through a metastable coiled-coil to mediate autophagy.
abstract: ATG14 binding to BECN/Beclin homologs is essential for autophagy, a critical catabolic homeostasis pathway. Here, we show that the α-helical, coiled-coil domain (CCD) of BECN2, a recently identified mammalian BECN1 paralog, forms an antiparallel, curved homodimer with seven pairs of nonideal packing interactions, while the BECN2 CCD and ATG14 CCD form a parallel, curved heterodimer stabilized by multiple, conserved polar interactions. Compared to BECN1, the BECN2 CCD forms a weaker homodimer, but binds more tightly to the ATG14 CCD. Mutation of nonideal BECN2 interface residues to more ideal pairs improves homodimer self-association and thermal stability. Unlike BECN1, all BECN2 CCD mutants bind ATG14, although more weakly than wild type. Thus, polar BECN2 CCD interface residues result in a metastable homodimer, facilitating dissociation, but enable better interactions with polar ATG14 residues stabilizing the BECN2:ATG14 heterodimer. These structure-based mechanistic differences in BECN1 and BECN2 homodimerization and heterodimerization likely dictate competitive ATG14 recruitment.
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota, 58108-6050.
authors.forename: Minfei
authors.initials: M
authors.lastname: Su
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota, 58108-6050.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota, 58108-6050.
authors.forename: Shane
authors.initials: S
authors.lastname: Wyborny
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Northeastern Collaborative Access Team, Argonne National Laboratory, Argonne, Illinois, 60439.
authors.forename: David
authors.initials: D
authors.lastname: Neau
authors.affiliation: Biophysics Collaborative Access Team/Illinois Institute of Technology, Advanced Photon Source, Argonne National Laboratory, Argonne, Illinois, 60439.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Chakravarthy
authors.affiliation: Center for Autophagy Research, Department of Internal Medicine and Howard Hughes Medical Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas, 75390.
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota, 58108-6050.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Colbert
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota, 58108-6050.
authors.forename: Sangita C
authors.initials: SC
authors.lastname: Sinha
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071183:Autophagy-Related Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
chemical_list: C539000:ATG14 protein, human; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; C584110:BECN2 protein, human; D047908:Intracellular Signaling Peptides and Proteins
keywords: ATG14; BECN2; BECN2:ATG14 heterodimer; autophagy; coiled-coil domain