7YIS

Crystal structure of N-terminal PH domain of ARAP3 protein in complex with inositol 1,3,4,5-tetrakisphosphate

Summary for 7YIS

• Entry DOI: 10.2210/pdb7yis/pdb
• Descriptor: Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3, (2R)-3-{[(S)-{[(2S,3R,5S,6S)-2,6-DIHYDROXY-3,4,5-TRIS(PHOSPHONOOXY)CYCLOHEXYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-2-(1-HYDROXY BUTOXY)PROPYL BUTYRATE (2 entities in total)
• Functional Keywords: arap3, ph domain, complex, inositol 1, 3, 4, 5-tetrakisphosphate, cytosolic protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 13773.29

Authors

Zhang, Y.J.,Liu, Y.R.,Wu, B. (deposition date: 2022-07-18, release date: 2023-05-03, Last modification date: 2023-11-29)

Primary citation

Zhang, Y.,Ge, L.,Xu, L.,Liu, Y.,Wang, J.,Liu, C.,Zhao, H.,Xing, L.,Wang, J.,Wu, B.
Structural Insights Uncover the Specific Phosphoinositide Recognition by the PH1 Domain of Arap3.
Int J Mol Sci, 24:-, 2023

PubMed Abstract: Arap3, a dual GTPase-activating protein (GAP) for the small GTPases Arf6 and RhoA, plays key roles in regulating a wide range of biological processes, including cancer cell invasion and metastasis. It is known that Arap3 is a PI3K effector that can bind directly to PI(3,4,5)P3, and the PI(3,4,5)P3-mediated plasma membrane recruitment is crucial for its function. However, the molecular mechanism of how the protein recognizes PI(3,4,5)P3 remains unclear. Here, using liposome pull-down and surface plasmon resonance (SPR) analysis, we found that the N-terminal first pleckstrin homology (PH) domain (Arap3-PH1) can interact with PI(3,4,5)P3 and, with lower affinity, with PI(4,5)P2. To understand how Arap3-PH1 and phosphoinositide (PIP) lipids interact, we solved the crystal structure of the Arap3-PH1 in the apo form and complex with diC4-PI(3,4,5)P3. We also characterized the interactions of Arap3-PH1 with diC4-PI(3,4,5)P3 and diC4-PI(4,5)P2 in solution by nuclear magnetic resonance (NMR) spectroscopy. Furthermore, we found overexpression of Arap3 could inhibit breast cancer cell invasion in vitro, and the PIPs-binding ability of the PH1 domain is essential for this function.

PubMed: 36674645
DOI: 10.3390/ijms24021125

Experimental method

X-RAY DIFFRACTION (3.3 Å)