Inter-organelle ER-endolysosomal contact sites in metabolism and disease across evolution

Figures & data

Table 1. Location, proposed functions, and associated diseases of ER-organelle MCS proteins.

Protein
S. cerevisiae	D. melanogaster	H. sapiens	Observed Membrane Contact Site(s)	Proposed Function(s)	Disease(s) Associated	References
Tricalbin	Esyt2	E-Syts	ER-PM (yeast, human)	ER-PM tethering, potential role in non-vescicular lipid transport		Tavassoli, S. et al., 2013
Scs2/22	VAP	VAP-A/B (ALS8)	ER-PM (yeast)	ER-PM tethering, recruitment of FFAT motif-containing proteins	ALS disease	Nishimura, A. L. et al., 2004
Ist2	Axs?	TMEM16/Ano family	ER-PM (yeast)	ER-PM tethering, possible channel activity	defects in chromosomal segregation in D. melanogaster
Nvj1	n/a	n/a	ER-vacuole (yeast)	ER-vac tethering, essential for Piecemeal Autophagy of the Nucleus (PMN)		Pan, X. et al., 2000
Vac8	n/a	n/a	ER-vacuole (yeast)	ER-vac tethering, vacuole inheritence		Pan, X. et al., 2000
Nvj2	CG43783	HT008/Tex2	ER-vacuole (yeast)	ER-vacuole tethering(?); possible role in lipid trafficking via its SMP domain		Toulmay, A. & Prinz, W. A., 2012
Tsc13	Sc2?	TECR	ER-vacuole (yeast)	enoyl reductase, generates very long chain fatty acids (VLCFAs); mutants in humans affect sphingolipid metabolism	essential in flies; mutants in mouse models	Abe, K. et al., 2013; Kvam, E. et al., 2005.
Mdm1	Snz	Snx13,14,19, 25	ER-vacuole (yeast)	ER-vacuole, comunication and lipid metabolism in yeast, and possible roles in obesity, aging, and neurological disease in metazoans	snz-deficienct fruit flies exhibit lifespan extension and obesity; human SNX14-deficiency is linked to cerebellar ataxia with intellectual disability	Henne, W. M. et al., 2015; Suh, et al. 2008; Thomas, et al., 2014
		Protrudin	ER-endosome (human)	endosomal migration,
Lam6/Ltc1	CG34394?	STARD3/STARD3NL	ER-vacuole/ER-mitochondria (yeast)	StART-like domain containing sterol-binding protein; possible role in inter-organelle sterol shuttling	loss of mammalian homologs linked to diseases of cholesterol homeostasis and breast cancer (MLN64/STARD3)	Alpy, F. et al., 2013; Elbaz-Alon, Y. et al., 2015; Murley, A. et al., 2015
Vps13	VPS13A	VPS13A/CHAC; VPS13B/COH	vacuole-mitochondria; ER-vacuole (yeast)	unknown, gain-of-function mutants can bypass loss of ERMES function in yeast	VPS13A: chorea-acanthocytosis; VPS13B: Cohen Syndrome	Velayos-Baeza, A. et al., 2004
Osh1-7	OSBPs	ORPs	ER-PM (Osh6 yeast; Orp5/8 human); ER-vacuole (Osh1)	sterol and phospholipid-binding proteins, which shuttle lipids including PS and PI4P at multiple membrane contact sites	links to defects in phosholipid and cholesterol homeostasis diseases	Olkkonen, V. M. et al., 2012
	dSTIM	STIM1	ER-PM	coordinates store operated calcium entry (SOCE) at ER-PM contact sites	combined immuno-deficiency (CID) in humans, bristle development in flies	Eid, J.-P., et al., 2008

Figure 1. Domain architecture of proteins implicated in ER-endolysosomal membrane contact sites. Protein orthologs among Saccharomyces cerevisiae (Sc top), Drosophila melanogaster (Dm, middle) and Homo sapiens (Hs, bottom) are depicted. Abbreviations: PHg, Pleckstrin homology gram; MENTAL, MLN64 N-terminal alignment; StART, StAR-related Lipid Transfer; PH, Pleckstrin homology; OSBP, Oxysterol binding domain; PXA, PX-Associated; RGS, Regulator of G-protein Signaling; PX, Phox Homology; MSP, Major Sperm Protein; SMP, Synaptotagmin-like mitochondrial lipid-binding protein; DUF, domain of unknown function.

Figure 2. Three-dimensional structure of LTPs showing the protein backbone (gray ribbon representation) and the bound lipid (purple sphere representation) (a) The crystal structure of the yeast oxysterol-related domain ORD of oxysterol binding protein (OSBP) homolog 4 (Osh4) in complex with 25-hydroxycholesterol (PDB: 1ZHX). (b) The crystal structure of CERT (STAR)-related transfer (STARt) domain in complex with C16-ceramide (PDB: 2E3P). (c) The crystal structure of extended-synaptotagmin 2 (E-syt2) SMP domain in complex with TritonX-100 and DOPE (PDB: 4P42).