7cyz

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The structure of human ORP3 OSBP-related domain

Structural highlights

7cyz 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 2.1Å
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

Oxysterol-binding protein (OSBP) and its related protein (ORP) constitute a conserved family of lipid transfer proteins (LTPs). ORPs have been implicated as intracellular lipid exchanger and sensor in recent years, which regulate the lipid homeostasis and signal pathway. OSBP-related protein 3 plays key role in controlling cell adhesion and migration and could be developed as the drug target for cancer therapy. Here, we report the crystal structures of human ORP3 ORD to 2.1 A and ORD-PI4P complex to 3.2 A. The binding assay in vitro confirms the ORP3 has the capability of PI4P binding. This study further verifies that the PI4P is the common ligand of all ORPs and ORPs should be the lipid exchanger in membrane contact sites(MCS).

The crystal structure of ORP3 reveals the conservative PI4P binding pattern.,Dong X, Wang Z, Ye S, Zhang R Biochem Biophys Res Commun. 2020 Sep 3;529(4):1005-1010. doi:, 10.1016/j.bbrc.2020.06.090. Epub 2020 Jul 30. PMID:32819557^[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
↑ Dong X, Wang Z, Ye S, Zhang R. The crystal structure of ORP3 reveals the conservative PI4P binding pattern. Biochem Biophys Res Commun. 2020 Sep 3;529(4):1005-1010. PMID:32819557 doi:10.1016/j.bbrc.2020.06.090