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BECN2 is a mammal-specific homolog of BECN1. Both proteins serve as a scaffolding molecule in the class III phosphatidylinositol 3-kinase complex (PtdIns3K) to promote macroautophagy/autophagy and endolysosomal trafficking. Our previous studies have shown that the BECN1 coiled-coil domain forms a metastable homodimer and readily self-dissociate to form the BECN1-ATG14 or BECN1-UVRAG coiled-coil complex as part of the scaffolding “arm” of the PtdIns3K complex. Here we report the crystal structure of the BECN2 coiled-coil domain, which forms a metastable homodimer similar to BECN1 but shows reduced stability and large deviation from the ideal coiled-coil geometry due to extra “imperfect” residues. We also report the crystal structure of BECN2-ATG14 coiled-coil complex, which is structurally similar to the BECN1-UVRAG coiled-coil complex we reported previously but functionally distinct. The potent BECN2-ATG14 interaction is selectively critical for endolysosomal degradation of the GPRASP1-associated DRD2/D2R but shows limited effect on EGFR, a cargo that depends on the BECN1-UVRAG interaction. We designed stapled peptides that selectively interacted with the BECN2 coiled-coil domain to enhance the BECN2-ATG14 or BECN1-UVRAG interaction. One such peptide specifically promoted BECN2-dependent processes including autophagy and endolysosomal degradation of DRD2/D2R but did not affect BECN1-dependent EGFR degradation. Our findings suggest that, despite high sequence identity to BECN1, BECN2 coiled-coil domain has unique structural features and the BECN2-ATG14 interaction selectively promotes autophagic or endolysosomal degradation of BECN2-specific cargos including GPRASP1-associated GPCRs. AMBRA1 		autophagy and beclin 1 regulator 1; ATG14 		autophagy related 14; ATG5			autophagy related 5; ATG7			autophagy related 7; BECN1		beclin 1; BECN2		beclin 2; CC			coiled-coil; CQ			chloroquine CNR1/CB1R		cannabinoid receptor 1 DAPI			4ʹ,6-diamidino-2-phenylindole; dCCD 			delete CCD; DRD2/D2R		dopamine receptor D2 GPRASP1/GASP1 	G protein-coupled receptor associated sorting protein 1 GPCR			G-protein coupled receptor; ITC			isothermal titration calorimetry; IP			immunoprecipitation; KD 			knockdown; KO 			knockout; MAP1LC3/LC3 	microtubule associated protein 1 light chain 3; NRBF2		nuclear receptor binding factor 2; OPRD1/DOR		opioid receptor delta 1 PIK3C3/VPS34 	phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15 	phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K 		class III phosphatidylinositol 3-kinase; PtdIns3P 		phosphatidylinositol-3-phosphate; RUBCN		rubicon autophagy regulator; SQSTM1/p62 		sequestosome 1; UVRAG 		UV radiation resistance associated; VPS 			vacuolar protein sorting; WT 			wild type.

The potent BECN2-ATG14 coiled-coil interaction is selectively critical for endolysosomal degradation of GPRASP1/GASP1-associated GPCRs