Characterization of the SAM domain of the PKD-related protein ANKS6 and its interaction with ANKS3

BMC Structural Biology

James U Bowie¹  Sigrid Hoffman²  Duilio Cascio¹  Mary Jane Knight¹  Catherine N Leettola¹ 

[1] Department of Chemistry and Biochemistry, UCLA-DOE Institute of Genomics and Proteomics, Molecular Biology Institute, University of California, Los Angeles, Boyer Hall 611 Charles E. Young Dr. E, Los Angeles, California 90095-1570, USA;Medical Research Centre, Klinikum Mannheim, University of Heidelberg, D-68167 Mannheim, Germany

关键词: Crystal structure;    Polymerization;    Protein-protein interaction;    Polycystic kidney disease;   

Others  :  1090863
DOI  :  10.1186/1472-6807-14-17

 received in 2014-06-28, accepted in 2014-06-30,  发布年份 2014

【 摘 要 】

Background

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder leading to end-stage renal failure in humans. In the PKD/Mhm(cy/+) rat model of ADPKD, the point mutation R823W in the sterile alpha motif (SAM) domain of the protein ANKS6 is responsible for disease. SAM domains are known protein-protein interaction domains, capable of binding each other to form polymers and heterodimers. Despite its physiological importance, little is known about the function of ANKS6 and how the R823W point mutation leads to PKD. Recent work has revealed that ANKS6 interacts with a related protein called ANKS3. Both ANKS6 and ANKS3 have a similar domain structure, with ankyrin repeats at the N-terminus and a SAM domain at the C-terminus.

Results

The SAM domain of ANKS3 is identified as a direct binding partner of the ANKS6 SAM domain. We find that ANKS3-SAM polymerizes and ANKS6-SAM can bind to one end of the polymer. We present crystal structures of both the ANKS3-SAM polymer and the ANKS3-SAM/ANKS6-SAM complex, revealing the molecular details of their association. We also learn how the R823W mutation disrupts ANKS6 function by dramatically destabilizing the SAM domain such that the interaction with ANKS3-SAM is lost.

Conclusions

ANKS3 is a direct interacting partner of ANKS6. By structurally and biochemically characterizing the interaction between the ANKS3 and ANKS6 SAM domains, our work provides a basis for future investigation of how the interaction between these proteins mediates kidney function.

【 授权许可】

   
2014 Leettola et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Wilson PD: Polycystic kidney disease. N Engl J Med 2004, 350:151-164.
• [2]Chapin HC, Caplan MJ: The cell biology of polycystic kidney disease. J Cell Biol 2010, 191:701-710.
• [3]Torres VE, Harris PC, Pirson Y: Autosomal dominant polycystic kidney disease. The Lancet 2007, 369:1287-1301.
• [4]Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J Med 1993, 329:332-342.
• [5]Ariza M, Alvarez V, Marin R, Aguado S, López-Larrea C, Alvarez J, Menéndez MJ, Coto E: A family with a milder form of adult dominant polycystic kidney disease not linked to the PKD1 (16p) or PKD2 (4q) genes. J Med Genet 1997, 34:587-589.
• [6]Hanaoka K, Qian F, Boletta A, Bhunia AK, Piontek K, Tsiokas L, Sukhatme VP, Guggino WB, Germino GG: Co-assembly of polycystin-1 and −2 produces unique cation-permeable currents. Nature 2000, 408:990-994.
• [7]Nagao S, Kugita M, Yoshihara D, Yamaguchi T: Animal models for human polycystic kidney disease. Exp Anim 2012, 61:477-488.
• [8]Guay-Woodford LM: Murine models of polycystic kidney diease: molecular and therapeutic insights. Am J Physiol - Ren Physiol 2003, 285:F1034-F1049.
• [9]Schäfer K, Gretz N, Bader M, Oberbäumer I, Eckardt K-U, Kriz W, Bachmann S: Characterization of the Han:SPRD rat model for hereditary polycystic kidney disease. Kidney Int 1994, 46:134-152.
• [10]Gretz N, Kränzlin B, Pey R, Schieren G, Bach J, Obermüller N, Ceccherini I, Klöting I, Rohemeiss P, Bachmann S, Hafner M: Rat models of autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 1996, 11:46-51.
• [11]Brown JH, Bihoreau M-T, Hoffmann S, Kränzlin B, Tychinskaya I, Obermüller N, Podlich D, Boehn SN, Kaisaki PJ, Megel N, Danoy P, Copley RR, Broxholme J, Witzgall R, Lathrop M, Gretz N, Gauguier D: Missense mutation in sterile α motif of novel protein samcystin is associated with polycystic kidney disease in (cy/+) rat. J Am Soc Nephrol 2005, 16:3517-3526.
• [12]Neudecker S, Walz R, Menon K, Maier E, Bihoreau M-T, Obermüller N, Kränzlin B, Gretz N, Hoffmann SC: Transgenic overexpression of Anks6(p.R823W) causes polycystic kidney disease in rats. Am J Pathol 2010, 177:3000-3009.
• [13]Hoff S, Halbritter J, Epting D, Frank V, Nguyen T-MT, van Reeuwijk J, Boehlke C, Schell C, Yasunaga T, Helmstädter M, Mergen M, Filhol E, Boldt K, Horn N, Ueffing M, Otto EA, Eisenberger T, Elting MW, van Wijk JAE, Bockenhauer D, Sebire NJ, Rittig S, Vyberg M, Ring T, Pohl M, Pape L, Neuhaus TJ, Elshakhs NAS, Koon SJ, Harris PC, et al.: ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet 2013, 45:951-956.
• [14]Qiao F, Bowie JU: The many faces of SAM. Sci STKE 2005, 2005:re7.
• [15]Kim CA, Bowie JU: SAM domains: uniform structure, diversity of function. Trends Biochem Sci 2003, 28:625-628.
• [16]Harada BT, Knight MJ, Imai S, Qiao F, Ramachander R, Sawaya MR, Gingery M, Sakane F, Bowie JU: Regulation of enzyme localization by polymerization: polymer formation by the SAM domain of diacylglycerol kinase δ1. Structure 2008, 16:380-387.
• [17]Kim CA, Gingery M, Pilpa RM, Bowie JU: The SAM domain of polyhomeotic forms a helical polymer. Nat Struct Biol 2002, 9:453-457.
• [18]Kim CA, Phillips ML, Kim W, Gingery M, Tran HH, Robinson MA, Faham S, Bowie JU: Polymerization of the SAM domain of TEL in leukemogenesis and transcriptional repression. EMBO J 2001, 20:4173-4182.
• [19]Baron MK, Boeckers TM, Vaida B, Faham S, Gingery M, Sawaya MR, Salyer D, Gundelfinger ED, Bowie JU: An architectural framework that may lie at the core of the postsynaptic density. Science 2006, 311:531-535.
• [20]Stafford RL, Hinde E, Knight MJ, Pennella MA, Ear J, Digman MA, Gratton E, Bowie JU: Tandem SAM domain structure of human Caskin1: a presynaptic, self-assembling scaffold for CASK. Structure 2011, 19:1826-1836.
• [21]Di Pietro SM, Cascio D, Feliciano D, Bowie JU, Payne GS: Regulation of clathrin adaptor function in endocytosis: novel role for the SAM domain. EMBO J 2010, 29:1033-1044.
• [22]Knight MJ, Leettola C, Gingery M, Li H, Bowie JU: A human sterile alpha motif domain polymerizome. Protein Sci 2011, 20:1697-1706.
• [23]Ramachander R, Kim CA, Phillips ML, Mackereth CD, Thanos CD, McIntosh LP, Bowie JU: Oligomerization-dependent Association of the SAM Domains from Schizosaccharomyces pombe Byr2 and Ste4. J Biol Chem 2002, 277:39585-39593.
• [24]Qiao F, Song H, Kim CA, Sawaya MR, Hunter JB, Gingery M, Rebay I, Courey AJ, Bowie JU: Derepression by depolymerization: structural insights into the regulation of Yan by Mae. Cell 2004, 118:163-173.
• [25]Kwan JJ, Warner N, Pawson T, Donaldson LW: The solution structure of the S.cerevisiae Ste11 MAPKKK SAM Domain and its partnership with Ste50. J Mol Biol 2004, 342:681-693.
• [26]Grimshaw SJ, Mott HR, Stott KM, Nielsen PR, Evetts KA, Hopkins LJ, Nietlispach D, Owen D: Structure of the sterile α Motif (SAM) domain of the saccharomyces cerevisiae mitogen-activated protein kinase pathway-modulating protein STE50 and analysis of its interaction with the STE11 SAM. J Biol Chem 2003, 279:2192-2201.
• [27]Leone M, Cellitti J, Pellecchia M: The Sam domain of the lipid phosphatase Ship2 adopts a common model to interact with Arap3-Sam and EphA2-Sam. BMC Struct Biol 2009, 9:59.
• [28]Qiao F, Harada B, Song H, Whitelegge J, Courey AJ, Bowie JU: Mae inhibits Pointed-P2 transcriptional activity by blocking its MAPK docking site. EMBO J 2005, 25:70-79.
• [29]Zhang H, Xu Q, Krajewski S, Krajewska M, Xie Z, Fuess S, Kitada S, Pawlowski K, Godzik A, Reed JC: BAR: an apoptosis regulator at the intersection of caspases and Bcl-2 family proteins. PNAS 2000, 97:2597-2602.
• [30]Aviv T, Lin Z, Rendl LM, Sicheri F, Smibert CA: The RNA-binding SAM domain of Smaug defines a new family of post-transcriptional regulators. Nat Struct Biol 2003, 10:614-621.
• [31]Barrera FN, Poveda JA, González-Ros JM, Neira JL: Binding of the C-terminal sterile α Motif (SAM) domain of human p73 to lipid membranes. J Biol Chem 2003, 278:46878-46885.
• [32]Kim CA, Sawaya MR, Cascio D, Kim W, Bowie JU: Structural organization of a sex-comb-on-midleg/Polyhomeotic copolymer. J Biol Chem 2005, 280:27769-27775.
• [33]Rajakulendran T, Sahmi M, Kurinov I, Tyers M, Therrien M, Sicheri F: CNK and HYP form a discrete dimer by their SAM domains to mediate RAF kinase signaling. Proc Natl Acad Sci 2008, 105:2836-2841.
• [34]Leone M, Cellitti J, Pellecchia M: NMR studies of a heterotypic Sam−Sam domain association: the interaction between the lipid phosphatase Ship2 and the EphA2 Receptor. Biochemistry 2008, 47:12721-12728.
• [35]Knight MJ, Joubert MK, Plotkowski ML, Kropat J, Gingery M, Sakane F, Merchant SS, Bowie JU: Zinc binding drives sheet formation by the SAM domain of diacylglycerol kinase δ. Biochemistry 2010, 49:9667-9676.
• [36]Gundelfinger ED, Boeckers TM, Baron MK, Bowie JU: A role for zinc in postsynaptic density asSAMbly and plasticity? Trends Biochem Sci 2006, 31:366-373.
• [37]Lawrence MS, Phillips KJ, Liu DR: Supercharging proteins can impart unusual resilience. J Am Chem Soc 2007, 129:10110-10112.
• [38]Grucza RA, Bradshaw JM, Mitaxov V, Waksman G: Role of electrostatic interactions in SH2 domain recognition: salt-dependence of tyrosyl-phosphorylated peptide binding to the tandem SH2 domain of the Syk kinase and the single SH2 domain of the Src kinase. Biochemistry 2000, 39:10072-10081.
• [39]Hileman RE, Jennings RN, Linhardt RJ: Thermodynamic analysis of the heparin interaction with a basic cyclic peptide using isothermal titration calorimetry. Biochemistry 1998, 37:15231-15237.
• [40]Nauli S, Farr S, Lee Y-J, Kim H-Y, Faham S, Bowie JU: Polymer-driven crystallization. Protein Sci 2007, 16:2542-2551.
• [41]Cogswell C, Price SJ, Hou X, Guay-Woodford LM, Flaherty L, Bryda EC: Positional cloning of jcpk/bpk locus of the mouse. Mamm Genome 2003, 14:242-249.
• [42]Stagner EE, Bouvrette DJ, Cheng J, Bryda EC: The polycystic kidney disease-related proteins Bicc1 and SamCystin interact. Biochem Biophys Res Commun 2009, 383:16-21.
• [43]Kugita M, Nishii K, Morita M, Yoshihara D, Kowa-Sugiyama H, Yamada K, Yamaguchi T, Wallace DP, Calvet JP, Kurahashi H, Nagao S: Global gene expression profiling in early-stage polycystic kidney disease in the Han:SPRD Cy rat identifies a role for RXR signaling. AJP Ren Physiol 2010, 300:F177-F188.
• [44]Senturia R, Faller M, Yin S, Loo JA, Cascio D, Sawaya MR, Hwang D, Clubb RT, Guo F: Structure of the dimerization domain of DiGeorge Critical Region 8. Protein Sci 2010, 19:1354-1365.
• [45]Schatz PJ, Cull MG, Martin EL, Gates CM: Screening of peptide libraries linked to lac repressor. Methods Enzymol 1996, 267:171-191.
• [46]Malakhov MP, Mattern MR, Malakhova OA, Drinker M, Weeks SD, Butt TR: SUMO fusions and SUMO-specific protease for efficient expression and purification of proteins. J Struct Funct Genomics 2004, 5:75-86.
• [47]Kabsch W: XDS. Acta Crystallogr D Biol Crystallogr 2010, 66:125-132.
• [48]Pape T, Schneider TR: HKL2MAP : a graphical user interface for macromolecular phasing with SHELX programs. J Appl Crystallogr 2004, 37:843-844.
• [49]Sheldrick GM: Experimental phasing with SHELXC/D/E : combining chain tracing with density modification. Acta Crystallogr D Biol Crystallogr 2010, 66:479-485.
• [50]Winn MD, Ballard CC, Cowtan KD, Dodson EJ, Emsley P, Evans PR, Keegan RM, Krissinel EB, Leslie AGW, McCoy A, McNicholas SJ, Murshudov GN, Pannu NS, Potterton EA, Powell HR, Read RJ, Vagin A, Wilson KS: Overview of the CCP 4 suite and current developments. Acta Crystallogr D Biol Crystallogr 2011, 67:235-242.
• [51]Adams PD, Afonine PV, Bunkóczi G, Chen VB, Davis IW, Echols N, Headd JJ, Hung L-W, Kapral GJ, Grosse-Kunstleve RW, McCoy AJ, Moriarty NW, Oeffner R, Read RJ, Richardson DC, Richardson JS, Terwilliger TC, Zwart PH: PHENIX : a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 2010, 66:213-221.
• [52]Emsley P, Lohkamp B, Scott WG, Cowtan K: Features and development of Coot. Acta Crystallogr D Biol Crystallogr 2010, 66:486-501.
• [53]Karplus PA, Diederichs: Linking crystallographic model and data quality. Science 2012, 336:1030-1033.
• [54]McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ: Phaser crystallographic software. J Appl Crystallogr 2007, 40:658-674.
• [55]Laskowski RA, MacArthur MW, Moss DS, Thornton JM: PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr 1993, 26:283-291.
• [56]Colovos C, Yeates TO: Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci 1993, 2:1511-1519.
• [57]Bowie JU, Lüthy R, Eisenberg D: A method to identify protein sequences that fold into a known three-dimensional structure. Science 1991, 253:164-170.
• [58]Schrödinger LLC: The PyMOL Molecular Graphics System, Version 1.3. 2010.
• [59]Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA: Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci 2001, 98:10037-10041.
• [60]Krissinel E, Henrick K: Inference of macromolecular assemblies from crystalline state. J Mol Biol 2007, 372:774-797.