Beclin 1-Vps34 complex architecture: Understanding the nuts and bolts of therapeutic targets

doi:10.1007/s11515-015-1374-y

Front. Biol.

2015, Vol. 10

Issue (5) : 398-426 https://doi.org/10.1007/s11515-015-1374-y

REVIEW

Beclin 1-Vps34 complex architecture: Understanding the nuts and bolts of therapeutic targets

Deanna H. Morris¹,Calvin K. Yip²,Yi Shi³,Brian T. Chait³,Qing Jun Wang^1,^4,^5,^*(

)

1. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA
2. Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada V6T1Z3, USA
3. Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, NY 10065, USA
4. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA
5. Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA

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Abstract

Autophagy is an important lysosomal degradation pathway that aids in the maintenance of cellular homeostasis by breaking down and recycling intracellular contents. Dysregulation of autophagy is linked to a growing number of human diseases. The Beclin 1-Vps34 protein-protein interaction network is critical for autophagy regulation and is therefore essential to cellular integrity. Manipulation of autophagy, in particular via modulation of the action of the Beclin 1-Vps34 complexes, is considered a promising route to combat autophagy-related diseases. Here we summarize recent findings on the core components and structural architecture of the Beclin 1-Vps34 complexes, and how these findings provide valuable insights into the molecular mechanisms that underlie the multiple functions of these complexes and for devising therapeutic strategies.

Keywords Beclin 1 Vps34 Nrbf2 complex structure CX-MS EM inhibitor drug design

Corresponding Author(s): Qing Jun Wang

Just Accepted Date: 22 October 2015 Online First Date: 23 October 2015 Issue Date: 30 October 2015

Cite this article:

Deanna H. Morris,Calvin K. Yip,Yi Shi, et al. Beclin 1-Vps34 complex architecture: Understanding the nuts and bolts of therapeutic targets[J]. Front. Biol., 2015, 10(5): 398-426.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-015-1374-y
https://academic.hep.com.cn/fib/EN/Y2015/V10/I5/398

Fig.1 A schematic of the autophagy pathway with the involvement of the Beclin 1-Vps34 class III PI(3)K complexes identified. The core class III PI(3)K complexes consist of Beclin 1, Vps34, and Vps15. The Atg14L-containing Beclin 1-Vps34 complex marks the sites at which the phagophores/isolation membranes form to enclose the cytoplasmic contents to be degraded. The phagophores subsequently elongate and seal off to form mature autophagosomes. Autophagosome maturation, particularly autophagosome fusion with the lysosome, is facilitated by the UVRAG-containing Beclin 1-Vps34 complex. The inner membranes of the autophagosomes and their contents are degraded and recycled to maintain cellular homeostasis. The interaction of Rubicon with the UVRAG-containing Beclin 1-Vps34 complex blocks the fusion between autophagosomes and lysosomes. In addition, the UVRAG-containing Beclin 1-Vps34 complex also regulates the tubule scission step during autophagic lysosome reformation.

Tab.1 Summary of reported structures for Beclin 1-Vps34 complex components

Fig.2 Domain structures of the proteins associated with the human Beclin 1-VPS34 complexes. Abbreviations: BH3, Bcl-2 homology 3; CCD, coiled-coil domain; ECD, evolutionarily conserved domain; MIT, microtubule-interacting and trafficking.

Fig.3 Currently available structural information of the Atg14L-containing, autophagic Beclin 1-Vps34 class III PI(3)K complex I (PI3KC3-C1). PI3KC3-C1 consists of four components: Atg14L, Beclin 1, Vps34, and Vps15. The V-shaped 3D reconstruction of human PI3KC3-C1 was determined by single-particle EM (EMDB: EMD-2846). Vps15 is thought to be the scaffolding subunit and the locations of its protein kinase (cyan), HEAT (blue), and WD-40 (purple) domains are colored in the EM-based 3D model. Thus far, the only available high-resolution structural information for this protein came from crystallographic analysis of yeast Vps15 WD-40 domain (PDB: 3GRE, residues 1031–1454). The catalytic subunit of PI3KC3-C1 is Vps34, which produces PtdIns(3)P at the autophagosome, endosome and lysosome membranes. The crystal structure of the helical and catalytic domains (“HELCAT”) of human VPS34 in complex with the selective inhibitor PIK-III has been recently determined (PDB:4PH4, residues 293-871 in red, inhibitor in green). Beclin1, which plays a central role in regulating the activity of PI3KC-C1, contains three functional domains: the N-terminal BH3 domain (PDB: 2P1L, residues 107-135 for human), the central CCD (PDB: 3Q8T, residues 144-269 for rat), and the ECD (PDB: 4DDP, residues 248-450 for human). The approximate locations of the Beclin 1 ECD in the context of the full complex, as determined by EM-based labeling, is colored in green in the 3D model. The positions of Vps34 C2 domain and the N-termini of Atg14L and Beclin 1 are colored in orange and gray, respectively. Nrbf2, although recently shown to be a subunit of the PI3KC-C1, was not included in the single-particle EM study. However, the structure of the N-terminal MIT domain of mouse Nrbf2 has previously been determined by NMR spectroscopy (PDB: 2CRB, residues 4-86).

Component #1	Domain of Component #1	Component #2	Direct interaction	Detection assay	Reference	Confirmed by CX-MS(Shi et al., 2015)
Beclin 1(Atg6/Vps 30 in yeast)	Full length (h, 1–450)	Beclin 1	Direct interaction	Y2H	Matsunaga et al., 2009
Vps34		--	AP	Kihara et al., 2001; Matsunaga et al., 2009; Furuya et al., 2005; Liang et al., 2006; Sun et al., 2008; Yan et al., 2009; Zhong et al., 2009, 2014; Behrenda et al., 2010; Araki et al., 2013; Cao et al., 2014; Lu et al., 2014
Vps15		--	AP	Kihara et al., 2001; Itakura et al., 2008; Sun et al., 2008; Matsunaga et al., 2009; Zhong et al., 2009, 2014; Behrenda et al., 2010; Lu et al., 2014
Atg14L		Direct interaction	AP, Y2H	Kihara et al., 2001; Kametaka et al., 1998; Itakura et al., 2008; Sun et al., 2008; Matsunaga et al., 2009; Zhong et al., 2009, 2014; Behrenda et al., 2010; Lu et al., 2014
UVRAG/Vps38		Direct interaction	AP, Y2H	Kihara et al., 2001; Liang et al., 2006; Itakura et al., 2008; Sun et al., 2008; Matsunaga et al., 2009; Zhong et al., 2009, 2014; Behrenda et al., 2010; Lu et al., 2014
Nrbf2		--	AP	Zhong et al., 2009, 2014; Behrenda et al., 2010; Araki et al., 2013; Cao et al., 2014; Lu et al., 2014
BH3 domain
CCD	Beclin 1	Direct interaction	AP, analytical ultracentrifugation, in vitro binding, bimolecular fluorescence complementation assay	Li et al., 2012
	Vps34	--	AP	Liang et al., 2006	Y	Y
	Atg14L	Direct interaction	AP, analytical ultracentrifugation, in vitro binding	Sun et al., 2008; Matsunaga et al., 2009; Zhong et al., 2009; Li et al., 2012	Y
	UVRAG	Direct interaction	AP, analytical ultracentrifugation, in vitro binding	Liang et al., 2006; Sun et al., 2008; Matsunaga et al., 2009; Li et al., 2012	Y
ECD/BARA	Atg14L	--	AP	Zhong et al, 2009	Y
Vps34	--	AP	Furuya et al., 2005; Liang et al., 2006Noda et al., 2012
Vps34	Full length(1–887)	Beclin1	--	AP, in vitro binding	Kihara et al., 2001; Matsunaga et al., 2009; Furuya et al., 2005; Liang et al., 2006; Sun et al., 2008; Yan et al., 2009; Zhong et al., 2009, 2014; Behrenda et al., 2010; Araki et al., 2013; Cao et al., 2014; Lu et al., 2014
Vps15		Direct interaction	AP, crosslinking	Stack et al., 1993, 1995; Volinia et al., 1995; Panaretou et al., 1997; Matsunaga et al., 2009; Yan et al., 2009; Zhong et al., 2014; Behrenda et al., 2010; Araki et al., 2013; Cao et al., 2014;
Atg14L		--	AP	Kihara et al., 2001; Sun et al., 2008; Itakura et al., 2008; Matsunaga et al., 2009; Behrenda et al., 2010; Araki et al., 2013; Cao et al., 2014; Zhong et al., 2014;
UVRAG		--	AP	Itakura et al., 2008; Matsunaga et al., 2009; Yan et al., 2009; Behrenda et al., 2010; Araki et al., 2013; Cao et al., 2014; Zhong et al., 2014;
Nrbf2		--	AP	Behrenda et al., 2010; Araki et al., 2013; Cao et al., 2014; Lu et al., 2014; Zhong et al., 2014
C2 domain	Beclin 1	--	AP	Liang et al., 2006; Itakura et al., 2008	Y	Y
	Atg14L	--	AP	Itakura et al., 2008	Y	Y
	UVRAG	--	AP	Itakura et al., 2008	Y	Y
Helical domain
Lipid kinase domain	Vps15	--	Y2H, functional assays (e.g., CPY sorting or maturation, PI(3)P levels)	(yeast) Volinia et al., 1995		Y
Vps15	Full length(1–1358)	Beclin 1	--	AP	Kihara et al., 2001; Itakura et al., 2008; Sun et al., 2008; Matsunaga et al., 2009; Zhong et al., 2009, 2014; Behrends et al., 2010
Vps34		Direct interaction	AP, Y2H, crosslinking	Volinia et al., 1995; Panaretou et al., 1997; Matsunaga et al., 2009; Yan et al., 2009; Behrends et al., 2010; Cao et al., 2014; Zhong et al., 2014(yeast) Stack et al., 1993; Stack et al., 1995; Budovskaya et al., 2002; Matsunaga et al., 2009; Araki et al., 2013
Atg14L		--	AP	Itakura et al., 2008; Matsunaga et al., 2009; Behrends et al., 2010; Zhong et al., 2014
UVRAG		--	AP	Behrends et al., 2010
Nrbf2		Direct interaction	AP, in vitrobinding	Behrends et al., 2010; Araki et al., 2013; Cao et al., 2014; Lu et al., 2014; Zhong et al., 2014
Kinase domain	Vps34	Direct interaction	Y2H	(yeast) Budovskaya et al., 2002		Y
				Crosslinking	(yeast) Stack et al., 1995
Atg14	--	AP	(yeast) Heenan et al., 2009
HEAT domain	Vps34	--	Y2H	(yeast) Budovskaya et al., 2002
WD-40 domain	Atg14	--	AP	(yeast) Heenan et al., 2009
Nrbf2	--	In vitro binding	Cao et al., 2014
Atg14L (Atg14 in yeast)	Full length (1–492)	Beclin 1	Direct interaction	AP, Y2H	Kametaka et al., 1998; Kihara et al., 2001; Itakura et al., 2008; Sun et al., 2008; Matsunaga et al., 2009; Zhong et al., 2009, 2014; Behrends et al., 2010;
Vps34		--	AP	Kihara et al., 2001; Itakura et al., 2008; Sun et al., 2008; Matsunaga et al., 2009; Behrends et al., 2010; Araki et al., 2013; Cao et al., 2014; Zhong et al., 2014
Vps15		--	AP	Itakura et al., 2008; Matsunaga et al., 2009; Behrends et al., 2010; Zhong et al., 2014
Nrbf2		Direct interaction	AP, in vitro binding	Behrends et al., 2010; Araki et al., 2013; Cao et al., 2014; Lu et al., 2014; Zhong et al., 2014
Zinc finger
CCD1 (75–95)	Beclin 1	--	AP	Zhong et al., 2009; Lu et al., 2014		Y
	Vps34	--	AP	Zhong et al., 2009
	Nrbf2	--	AP	Lu et al., 2014; Zhong et al., 2014
CCD2 (148–178)	Beclin 1	--	AP	Zhong et al., 2009; Lu et al., 2014	Y
CCD (71–184 or 88–178)	Beclin 1	Direct interaction	AP, analytical ultracentrifugation, in vitro binding	Itakura et al., 2008; Sun et al., 2008; Matsunaga et al., 2009; Li et al., 2012	Y
Vps34	--	AP	Itakura et al., 2008	Y
UVRAG (Vps38 in yeast)	Full length (1–698)	Beclin 1	Direct interaction	AP, Y2H	Kihara et al., 2001; Liang et al., 2006; Itakura et al., 2008; Sun et al., 2008; Matsunaga et al., 2009; Zhong et al., 2009, 2014; Behrends et al., 2010;
Vps34		--	AP	Itakura et al., 2008; Matsunaga et al., 2009; Yan et al., 2009; Behrends et al., 2010; Araki et al., 2013; Cao et al., 2014; Zhong et al., 2014
Vps15		--	AP	Matsunaga et al., 2009; Behrends et al., 2010
Nrbf2		--	--	only shown in (Lu et al., 2014)
C2 domain
CCD	Beclin 1	Direct interaction	AP, analytical ultracentrifugation, in vitro	Liang et al., 2006; Sun et al., 2008; Li et al., 2012	Y
Vps34	--	binding	Y
Nrbf2 (Atg38 in yeast)	Full length(1–287)	Beclin 1	Weak direct	AP, Y2H (weak)	Zhong et al., 2009; Behrends et al., 2010; Araki et al., 2013; Cao et al., 2014; Lu et al., 2014; Zhong et al., 2014
Vps34	Weak direct	AP, Y2H (weak)	Behrends et al., 2010; Araki et al., 2013; Cao et al., 2014; Lu et al., 2014; Zhong et al., 2014
Vps15	Direct interaction	AP, in vitro binding	Araki et al., 2013; Cao et al., 2014; Lu et al., 2014; Zhong et al., 2014
Atg14L	Direct interaction	AP, in vitro binding, Y2H	Behrends et al., 2010; Araki et al., 2013; Cao et al., 2014; Lu et al., 2014; Zhong et al., 2014
UVRAG	--	AP	only shown in (Lu et al., 2014)
Nrbf2/Atg38	Direct interaction	AP, Y2H	Araki et al., 2013; Zhong et al., 2014
MIT domain (8–52) Yeast 1–80	Beclin 1	--	AP	Zhong et al., 2014
	Atg14L	--	AP	Lu et al., 2014
	Atg14	Direct interaction	Y2H	Araki et al., 2013
Yeast 1–120	Atg14	Direct interaction	Y2H, in vitro binding	Araki et al., 2013
Vps34	Direct interaction	Y2H, in vitro binding	Araki et al., 2013
CCD (167–215)	Nrbf2	Direct interaction	AP, Y2H	Araki et al., 2013; Zhong et al., 2014
Or yeast 121–226	Vps34	Direct interaction	Y2H	Araki et al., 2013

Tab.2 Summary of reported interactions among the Beclin 1-Vps34 complex key components including Beclin 1, Vps34, Vps15, Atg14L, UVRAG and Nrbf2

Vps34 inhibitor	Molecular structure	IC50 (in vitro)	IC50 (in vivo)	IC50 for other lipid kinases	IC50 for protein kinases	Reference	Patent by
Wortmannin	<InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fib-10374-qjw.doc_images\fib-10374-qjw-tb3fig1.jpg" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FIB-10374-QJW.doc_Images\FIB-10374-QJW-tb3fig1.tif" Format="TIFF" ScaleToFitHeight="36.0pt" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject>	1.8 – 4.0 nM	6 μM by counting GFP-2xFYVE puncta; 30 nM by overall proteolysis in rat hepatocytes	Wortmannin and its analogues are not inhibitors of Ptdlns-4-kinase (at conc. up to 32 µM).	Wortmannin and its analogues are not inhibitors of protein kinase C (at conc. up to 22 µM), c-Src tyrosine kinase (at conc. up to 5.5 µM), and phosphoinositide- specific phospholipase C (at conc. up to 0.27 mM).	Dowdle et al., 2014; Ronan et al., 2014; Blommaart et al., 1997; Powis et al., 1994
3-methyladenine (3-MA)	<InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fib-10374-qjw.doc_images\fib-10374-qjw-tb3fig2.jpg" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FIB-10374-QJW.doc_Images\FIB-10374-QJW-tb3fig2.tif" Format="TIFF" ScaleToFitHeight="36.0pt" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject>	~ 1 mM (at 50 µM ATP)	616 μM by counting GFP-2xFYVE puncta; 5 mM 3- MA inhibited 60% proteolysis in hepatocytes.			Dowdle et al., 2014; Blommaart et al., 1997; Seglen and Gordon, 1982
LY294002 (2-(4-morpholinyl)-8-phenylchromone)	<InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fib-10374-qjw.doc_images\fib-10374-qjw-tb3fig3.jpg" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FIB-10374-QJW.doc_Images\FIB-10374-QJW-tb3fig3.tif" Format="TIFF" ScaleToFitHeight="36.0pt" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject>	1.4 – 4.2 µM	10 µM by overall proteolysis in rat hepatocytes			Ronan et al., 2014; Blommaart et al., 1997; Vlahos et al., 1994
PIK-III	<InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fib-10374-qjw.doc_images\fib-10374-qjw-tb3fig4.jpg" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FIB-10374-QJW.doc_Images\FIB-10374-QJW-tb3fig4.tif" Format="TIFF" ScaleToFitHeight="36.0pt" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject>	18 nM	55 μM by counting GFP-2xFYVE puncta;	>1 μM for PI(3)Kα, PI(3)Kβ, PI(3)Kγ, PI(3)Kδ, PI4Kβ.	>9.1 μM for mTOR	Dowdle et al., 2014	Novartis
VPS34-IN1 (1-[{2-[(2-chloropyridin-4yl)amino]-4’-(cyclopropyl-methyl)-[4,5’-bipyrimi-din]-2’-yl}amino]-2-methylpropan-2-ol) (CAS registry number 1383716-33-3)	<InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fib-10374-qjw.doc_images\fib-10374-qjw-tb3fig5.jpg" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FIB-10374-QJW.doc_Images\FIB-10374-QJW-tb3fig5.tif" Format="TIFF" ScaleToFitHeight="36.0pt" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject>	25 nM	100 nM by counting GFP-2xFYVE puncta; 100 nM ~ 1 μM by SGK3 activity and T- loop/hydrophobi c motif phosphorylation	>1 μM for other lipid kinases: in the Dundee panel (19 lipid kinases, includes class I PI3Ks), the AstraZeneca panel (8 lipid kinases, includes class I) and ProQuinase panel (13 lipid kinases, includes class I and class II PI3Ks); did not significantly inhibit any of the lipid kinases tested including class I (p110α, p110β p110γ and p110δ) and all three members of the class II (PI3KC2α, PI3KC2β, PI3KC2γ) PI3Ks.	1 μM did not significantly inhibit the activity of any of the protein kinases in the Dundee panel (140 kinases) and the ProQinase panel (300 kinases)	Bago et al., 2014	Novartis(WO 2012085-815A1)
SAR405 ((8s)-9-[(5-Chloranylpyridin-3-yl)methyl]-2-[(3r)-3-Methylmorpholin-4-yl]-8-(Trifluoromethyl)-6,7,8,9a-Tetrahydro-3h-Pyrimido[1,2- A]pyrimidin-4-One) (CAS registry number1523406-39-4)	<InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fib-10374-qjw.doc_images\fib-10374-qjw-tb3fig6.jpg" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FIB-10374-QJW.doc_Images\FIB-10374-QJW-tb3fig6.tif" Format="TIFF" ScaleToFitHeight="36.0pt" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject>	1.2 nM (K_D=1.5 µM)	27 nM by counting GFP-2xFYVE puncta; 419 nM by counting % of cells with GFP-LC3 dots in response to starvation	In vitro:>10 μM for class I PI3Ks (p110α, p110β, p110γ and p110δ) and class II PI3Ks (PI3KC2α, PI3KC2β and PI3KC2γ); In vivo: 1 μM leads to 39%, 68%, and 63% inhibition of p110α, p110β and p110δ, respectively.	In vitro:>10 μM for mTOR; In vivo: 1 μM leads to 52% inhibition of SMG1, but not any other protein kinases. 10 μM did not affect Akt, S6, p53, and phosphorylation.	Ronan et al., 2014	Sanofi
Compound 31 ((2S)?8-[(3R)?3- Methylmorpholin-4- yl]-1-(3-methyl-2-oxobutyl)-2- (trifluoromethyl)-3,4-dihydro?2Hpyrimido[1,2?a]pyrimidin-6-one)	<InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fib-10374-qjw.doc_images\fib-10374-qjw-tb3fig7.jpg" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FIB-10374-QJW.doc_Images\FIB-10374-QJW-tb3fig7.tif" Format="TIFF" ScaleToFitHeight="36.0pt" ScaleToFitWidth="48.0pt" ScaleToFit="1"/></InlineMediaObject>	2 nM (K_D= 2.7±0.9 nM)	82 nM by counting GFP-2xFYVE puncta;	In vitro:>2 μM for class I PI3Ks (p110α, p110β, p110γ and p110δ); and>10 μM for class II PI3Ks (PI3KC2α and PI3KC2γ);	In vitro:>10 μM for mTOR; In vivo: 8.5 μM for Akt (@Ser473);	Pasquier et al., 2015	Sanofi

Tab.3 Summary of reported Vps34 inhibitors

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