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7dei

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Structure of human ORP3 ORD domain in complex with PI(4)P

Structural highlights

7dei is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

OSBL3_HUMAN Phosphoinositide-binding protein which associates with both cell and endoplasmic reticulum (ER) membranes (PubMed:16143324). Can bind to the ER membrane protein VAPA and recruit VAPA to plasma membrane sites, thus linking these intracellular compartments (PubMed:25447204). The ORP3-VAPA complex stimulates RRAS signaling which in turn attenuates integrin beta-1 (ITGB1) activation at the cell surface (PubMed:18270267, PubMed:25447204). With VAPA, may regulate ER morphology (PubMed:16143324). Has a role in regulation of the actin cytoskeleton, cell polarity and cell adhesion (PubMed:18270267). Binds to phosphoinositides with preference for PI(3,4)P2 and PI(3,4,5)P3 (PubMed:16143324). Also binds 25-hydroxycholesterol and cholesterol (PubMed:17428193).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Human ORP3 belongs to the oxysterol-binding protein (OSBP) family of lipid transfer proteins and is involved in lipid trafficking and cell signaling. ORP3 localizes to the ER-PM interfaces and is implicated in lipid transport and focal adhesion dynamics. Here, we report the 2.6-2.7 A structures of the ORD (OSBP-related domain) of human ORP3 in apo-form and in complex with phosphatidylinositol 4-phosphate. The ORP3 ORD displays a helix grip beta-barrel fold with a deep hydrophobic pocket which is conserved in the OSBP gene family. ORP3 binds PI(4)P by the residues around tunnel entrance and in the hydrophobic pocket, whereas it lacks sterol binding due to the narrow hydrophobic tunnel. The heterologous expression of the ORDs of human ORP3 or OSBP1 rescued the lethality of seven ORP (yeast OSH1-OSH7) knockout in yeast. In contrast, the PI(4)P-binding site mutant of ORP3 did not complement the OSH knockout cells. The N-terminal PH domain and FFAT motif of ORP3 are involved in protein targeting but are not essential in yeast complementation. This observation suggests that the essential function conserved in the ORPs of yeast and human is mediated by PI(4)P-binding of the ORD domain. This study suggests that the non-vesicular PI(4)P transport is a conserved function of all ORPs in eukaryotes.

Structure of human ORP3 ORD reveals conservation of a key function and ligand specificity in OSBP-related proteins.,Tong J, Tan L, Im YJ PLoS One. 2021 Apr 15;16(4):e0248781. doi: 10.1371/journal.pone.0248781., eCollection 2021. PMID:33857182^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lehto M, Hynynen R, Karjalainen K, Kuismanen E, Hyvarinen K, Olkkonen VM. Targeting of OSBP-related protein 3 (ORP3) to endoplasmic reticulum and plasma membrane is controlled by multiple determinants. Exp Cell Res. 2005 Nov 1;310(2):445-62. doi: 10.1016/j.yexcr.2005.08.003. Epub, 2005 Sep 6. PMID:16143324 doi:http://dx.doi.org/10.1016/j.yexcr.2005.08.003
↑ Suchanek M, Hynynen R, Wohlfahrt G, Lehto M, Johansson M, Saarinen H, Radzikowska A, Thiele C, Olkkonen VM. The mammalian oxysterol-binding protein-related proteins (ORPs) bind 25-hydroxycholesterol in an evolutionarily conserved pocket. Biochem J. 2007 Aug 1;405(3):473-80. PMID:17428193 doi:http://dx.doi.org/10.1042/BJ20070176
↑ Lehto M, Mayranpaa MI, Pellinen T, Ihalmo P, Lehtonen S, Kovanen PT, Groop PH, Ivaska J, Olkkonen VM. The R-Ras interaction partner ORP3 regulates cell adhesion. J Cell Sci. 2008 Mar 1;121(Pt 5):695-705. doi: 10.1242/jcs.016964. Epub 2008 Feb , 12. PMID:18270267 doi:http://dx.doi.org/10.1242/jcs.016964
↑ Weber-Boyvat M, Kentala H, Lilja J, Vihervaara T, Hanninen R, Zhou Y, Peranen J, Nyman TA, Ivaska J, Olkkonen VM. OSBP-related protein 3 (ORP3) coupling with VAMP-associated protein A regulates R-Ras activity. Exp Cell Res. 2015 Feb 15;331(2):278-91. doi: 10.1016/j.yexcr.2014.10.019. Epub, 2014 Oct 29. PMID:25447204 doi:http://dx.doi.org/10.1016/j.yexcr.2014.10.019
↑ Tong J, Tan L, Im YJ. Structure of human ORP3 ORD reveals conservation of a key function and ligand specificity in OSBP-related proteins. PLoS One. 2021 Apr 15;16(4):e0248781. doi: 10.1371/journal.pone.0248781., eCollection 2021. PMID:33857182 doi:http://dx.doi.org/10.1371/journal.pone.0248781