BECN2 interacts with ATG14 through a metastable coiled‐coil to mediate autophagy

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...

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Bibliographic Details
Published in:Protein science 2017-05, Vol.26 (5), p.972-984
Main Authors: Su, Minfei, Li, Yue, Wyborny, Shane, Neau, David, Chakravarthy, Srinivas, Levine, Beth, Colbert, Christopher L., Sinha, Sangita C.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Vesicular Transport - chemistry
Adaptor Proteins, Vesicular Transport - genetics
Adaptor Proteins, Vesicular Transport - metabolism
ATG14
Autophagy
Autophagy-Related Proteins - chemistry
Autophagy-Related Proteins - genetics
Autophagy-Related Proteins - metabolism
BECN2
BECN2:ATG14 heterodimer
coiled‐coil domain
Coils
Homeostasis
Homology
Humans
Intracellular Signaling Peptides and Proteins - chemistry
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Mutants
Packing
Phagocytosis
Protein Multimerization
Protein Structure, Quaternary
Protein Structure, Secondary
Recruitment
Residues
Self-association
Thermal stability
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Summary: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. PDB Code(s): 5K7B; 5K9L
ISSN:0961-8368
1469-896X
DOI:10.1002/pro.3140