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Tetrakisphosphate: a Novel Adaptor Protein Involved in Human Cerebral Cavernous Malformation

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Tetrakisphosphate: a Novel Adaptor Protein Involved in Human Cerebral Cavernous Malformation Biochemical and Biophysical Research Communications 399 (2010) 587–592 Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc Crystal structure of human programmed cell death 10 complexed with inositol-(1,3,4,5)-tetrakisphosphate: A novel adaptor protein involved in human cerebral cavernous malformation Jingjin Ding, Xiaoyan Wang, De-Feng Li, Yonglin Hu, Ying Zhang, Da-Cheng Wang * National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, People’s Republic of China article info abstract Article history: Programmed cell death 10 (PDCD10) is a novel adaptor protein involved in human cerebral cavernous Received 26 July 2010 malformation, a common vascular lesion mostly occurring in the central nervous system. By interacting Available online 1 August 2010 with different signal proteins, PDCD10 could regulate various physiological processes in the cell. The crystal structure of human PDCD10 complexed with inositol-(1,3,4,5)-tetrakisphosphate has been deter- Keywords: mined at 2.3 Å resolution. The structure reveals an integrated dimer via a unique assembly that has never Adaptor protein been observed before. Each PDCD10 monomer contains two independent domains: an N-terminal Programmed cell death 10 domain with a new fold involved in the tight dimer assembly and a C-terminal four-helix bundle domain Unique dimeric assembly that closely resembles the focal adhesion targeting domain of focal adhesion kinase. An eight-residue Conformational variability Phosphatidylinositide binding flexible linker connects the two domains, potentially conferring mobility onto the C-terminal domain, Binding partner recruitment resulting in the conformational variability of PDCD10. A variable basic cleft on the top of the dimer inter- face binds to phosphatidylinositide and regulates the intracellular localization of PDCD10. Two potential sites, respectively located on the two domains, are critical for recruiting different binding partners, such as germinal center kinase III proteins and the focal adhesion protein paxillin. Ó 2010 Elsevier Inc. All rights reserved. Introduction strin-homology (PH) domains, bind phosphatidylinositides and determine the localization of the corresponding adaptor proteins Adaptor proteins are attracting more interest due to their essen- [3]. tial roles in governing multi protein cross-talk and signaling spec- Programmed cell death 10 (PDCD10) was initially characterized ificity of numerous signal transduction pathways that mediate as a gene whose expression was upregulated upon the induction various physiological processes in the cell [1,2]. They can recruit of apoptosis in human myeloid cell lines [4]. Later, PDCD10 was different signal proteins to a specific location and regulate the identified as the cerebral cavernous malformation 3 (CCM3) gene, interactions between these binding partners, thus driving the for- in which loss-of-function mutations could result in cerebral cavern- mation of larger signaling complexes. Adaptor proteins tend to lack ous malformation (CCM) [5]. CCM is a common vascular lesion found any intrinsic catalytic activity but instead consist of different pro- mostly in the central nervous system. Individuals with CCM may be tein–protein and protein–lipid-interaction modules. For example, under a risk of focal hemorrhage, resulting in headaches, seizures the Src-homology 2 (SH2) domains recognize specific sequences and stroke in midlife [6]. The protein encoded by the PDCD10 gene within their binding partners that contain phosphotyrosine resi- was predicted to be an adaptor protein because it lacks any known dues, and Src-homology 3 (SH3) domains bind proline-rich se- catalytic domains. As a novel adaptor protein, PDCD10 was identi- quences within specific peptide sequence contexts of their fied as a component of the larger CCM signaling complex, which binding partners. Lipid-interaction modules, such as the pleck- consists of KRIT1 (Krev1/Rap1A Interaction Trapped 1, also known as CCM1), OSM (Osmosensing Scaffold for MEKK3, also known as CCM2) and PDCD10 [7,8]. Both proliferative and apoptotic functions Abbreviations: PDCD10, programmed cell death 10; CCM, cerebral cavernous malformation; 4IP, inositol-(1,3,4,5)-tetrakisphosphate; SH2, Src-homology 2; SH3, have been identified for this adaptor protein [9,10]. Recently, Src-homology 3; PH, pleckstrin-homology; KRIT1, Krev1/Rap1A Interaction Trapped PDCD10 has been found to localize to the Golgi apparatus, forming 1; OSM, Osmosensing Scaffold for MEKK3; GCKIII, germinal center kinase III; FAT, a complex with proteins of the germinal center kinase III (GCKIII) focal adhesion targeting; MAD, multiple-wavelength anomalous dispersion. family, which are involved in signal pathways of cell orientation * Corresponding author. Address: National Laboratory of Biomacromolecules, and migration [11]. Although understanding of the physiological Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, People’s Republic of China. Fax: +86 10 64888560. role of PDCD10 has increased, the structural basis for the function E-mail address: [email protected] (D.-C. Wang). of PDCD10 remains unknown and is of great interest. 0006-291X/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2010.07.119 588 J. Ding et al. / Biochemical and Biophysical Research Communications 399 (2010) 587–592 Here we present the crystal structure of PDCD10 complexed Crystallization with inositol-(1,3,4,5)-tetrakisphosphate (4IP) and discuss the un- ique dimeric assembly, possible conformational variability and The crystallization experiments were conducted using the phosphatidylinositide binding of this novel adaptor protein. The hanging-drop vapor-diffusion method at 293 K with 2 ll drops potential sites of PDCD10 for binding partner recruitment are also containing 1 ll protein solution and 1 ll reservoir solution equili- investigated. brated over 0.5 ml reservoir solution. Initial crystallization screen- ing was performed using Index kit (Hampton Research). After two Material and methods days, two conditions produced microcrystals: (i) 3.0 M NaCl and 100 mM Bis–Tris pH 5.5 and (ii) 200 mM ammonium sulfate, 25% Cloning, expression, and purification (w/v) PEG 3350 and 100 mM Bis–Tris pH 5.5. Well-shaped crystals were obtained in the optimized conditions by varying the concen- The truncated DNA comprising residues 8–212 of the human tration of precipitants, the pH, and the type and concentration of PDCD10 gene (GenBank: NP_009148) was amplified from the re- additives. However, the crystals diffracted poorly to 8 Å on a Riga- verse transcriptase-polymerase chain reaction products of human ku FRE diffraction system using a Rigaku R-Axis IV++ image plate hemopoietic stem cell by PCR and subcloned into a pET22b(+) detector. In an attempt to produce better crystals, we added inosi- vector (Novagen) using Nde I and Xho I restriction sites. The recom- tol-(1,3,4,5)-tetrakisphosphate (4IP, Avanti Polar Lipids) to the pro- binant protein was overexpressed as a fusion protein with a tein to a final concentration of 5 mM and reset the crystallization C-terminal six-histidine tag in Escherichia coli BL21(DE3). The cells trials. Well-diffracting crystals of both the native protein and the were grown in LB medium supplemented with 100 lg/mL ampicil- SeMet derivative were obtained under the following condition: lin at 310 K until the culture reached an OD600 of 0.6, and expres- 30% (v/v) ethylene glycol, 100 mM sodium cacodylate pH 6.0. Dia- sion was induced with 0.5 mM IPTG at 289 K overnight. The mond-shaped crystals (300 Â 200 Â 200 lm) typically appeared in harvested cells were resuspended in lysis buffer (50 mM NaH2PO4, 24 h. pH 8.0; 300 mM NaCl; 10 mM imidazole) with 0.1 mM PMSF and lysed by sonication. The lysate was clarified by centrifugation Data collecting and processing and purified on a nickel-affinity column followed by size-exclusion chromatography using a Superdex 200 column (Amersham Phar- All diffraction data were collected at the beamline 17A (BL17A) macia). The purified protein was concentrated to 40 mg/ml and at the Photon Factory (Tsukuba, Japan) using an ADSC Quantum- stored in 20 mM Tris–HCl pH 8.0, 150 mM NaCl, 0.2 mM EDTA, 270 charge-coupled device (CCD) detector. Prior to data collection, 5 mM DTT at 193 K. The selenomethionine-substituted (SeMet) PDCD10 crystals were transferred to a cryoprotectant solution con- derivative was produced by expression in E. coli methionine auxo- taining 20% (v/v) dimethyl sulfoxide, 25% (v/v) ethylene glycol, trophic strain B834(DE3). The purification procedure of the SeMet 100 mM sodium cacodylate pH 6.0 and soaked for about 2 min. derivative was the same as that of the native protein. The crystals were then flash-frozen in a nitrogen-gas stream at Table 1 Data collection and structural refinement statistics. Data collection statistics Crystal Selenomethionine derivative Native Space group P41212 P41212 Cell parameters (Å) a = 90.34 a = 89.83 b = 90.34 b = 89.83 c = 114.14 c = 114.20 Wavelength (Å) 0.97888 (peak) 0.97928 (edge) 0.96405 (remote) 1.0000 Resolution range (last shell) (Å) 50.0–2.70 (2.85–2.70) 50.0–2.30 (2.42–2.30) Total reflections 256873 128264 128390 152206 Unique reflections 13582 13604 13615 21428 Completeness (last shell) 100% (100%) 100% (100%) 100% (100%) 99.9% (100%) Redundancy (last shell) 18.9 (19.4) 9.4 (9.7) 9.4 (9.7) 7.1 (7.3) I/(I) (last shell) 21.7 (8.3) 14.3 (4.8) 13.8 (4.2) 14.6 (5.8) Rsym (last shell) 9.8% (36.9%) 10.1% (42.5%) 10.3% (49.4%) 8.3% (31.7%) Refinement statistics Rwork 21.35% Rfree 26.41% Nonhydrogen atoms Protein atoms 3193 Water molecules 99 Heteroatoms 28 Average B factors (Å2) Protein 55.9 Solvent 56.84 Ligand 76.37 r.m.s. Deviations Bond lengths (Å) 0.005 Bond angles (°) 0.676 Chirality (Å) 0.051 Planarity (Å) 0.002 Dihedral angles (°) 18.192 Ramachandran plot statistics Favored regions 97.14% Allowed regions 2.86% Outlier regions 0% J.
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