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WW domain
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<h2 id="structure-and-ligands">Structure and ligands</h2> <p>The WW domain is one of the smallest <a href="/facts/Protein_module/oUpFcSsl">protein modules</a>, composed of only 40 amino acids, which mediates specific <a href="/facts/Protein-protein_interaction/etvm9Wmg">protein-protein interactions</a> with short <a href="/facts/Proline/x1ABSW5A">proline</a>-rich or proline-containing motifs.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> Named after the presence of two conserved <a href="/facts/Tryptophan/JcUxlxAh">tryptophans</a> (W), which are spaced 20-22 amino acids apart within the sequence,<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> the WW domain folds into a meandering triple-stranded <a href="/facts/Beta_sheet/B6mwwR6H">beta sheet</a>.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> The identification of the WW domain was facilitated by the analysis of two splice isoforms of <a href="/facts/YAP1/jl4okjo9">YAP</a> gene product, named YAP1-1 and YAP1-2, which differed by the presence of an extra 38 amino acids. These extra amino acids are encoded by a spliced-in <a href="/facts/Exon/8KWJtLuN">exon</a> and represent the second WW domain in YAP1-2 isoform.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p><p>The first structure of the WW domain was determined in solution by <a href="/facts/Nuclear_magnetic_resonance_spectroscopy_of_proteins/lCIXAFzQ">NMR</a> approach.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> It represented the WW domain of human YAP in complex with peptide ligand containing Proline-Proline-x–Tyrosine (PPxY where x = any amino acid) consensus motif.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> Recently, the YAP WW domain structure in complex with <a href="/facts/SMAD_(protein)/aIWIB7Nq">SMAD</a>-derived, PPxY motif-containing peptide was further refined.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Apart from the PPxY motif, certain WW domains recognize LPxY motif (where L is Leucine),<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> and several WW domains bind to phospho-Serine-Proline (p-SP) or phospho-Threonine-Proline (p-TP) motifs in a phospho-dependent manner.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> Structures of these WW domain complexes confirmed molecular details of <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a>-regulated interactions.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a><a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> There are also WW domains that interact with polyprolines that are flanked by arginine residues or interrupted by leucine residues, but they do not contain aromatic amino acids.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p> <h2 id="signaling-function">Signaling function</h2> <p>The WW domain is known to mediate regulatory protein complexes in various signaling networks, including the <a href="/facts/Hippo_signaling_pathway/4Xs0NBPk">Hippo signaling pathway</a>.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> The importance of WW domain-mediated complexes in signaling was underscored by the characterization of genetic syndromes that are caused by loss-of-function point mutations in the WW domain or its cognate ligand. These syndromes are Golabi-Ito-Hall syndrome of intellectual disability caused by missense mutation in a WW domain<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a><a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> and <a href="/facts/Liddle_syndrome/x7uzcdg5">Liddle syndrome</a> of <a href="/facts/Hypertension/wlAvBfcf">hypertension</a> caused by point mutations within PPxY motif.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> </p> <h2 id="examples">Examples</h2> <p>A large variety of proteins containing the WW domain are known. These include; <a href="/facts/Dystrophin/A23Wr8DM">dystrophin</a>, a multidomain cytoskeletal protein; <a href="/facts/Utrophin/KI0CQL14">utrophin</a>, a dystrophin-like protein; vertebrate YAP protein, substrate of LATS1 and LATS2 <a href="/facts/Serine-threonine_kinase/QKSTb82e">serine-threonine kinases</a> of the Hippo tumor suppressor pathway; <i>Mus musculus</i> (<a href="/facts/Mouse/6m1X7m0g">Mouse</a>) <a href="/facts/NEDD4/QTvx0akB">NEDD4</a>, involved in the embryonic development and differentiation of the central nervous system; <i><a href="/facts/Saccharomyces_cerevisiae/sX9MGFrz">Saccharomyces cerevisiae</a></i> (Baker's yeast) RSP5, similar to NEDD4 in its molecular organization; <i>Rattus norvegicus</i> (<a href="/facts/Rat/5rn6uEKM">Rat</a>) <a href="/facts/APBB1/V0GLx42q">FE65</a>, a transcription-factor activator expressed preferentially in brain; <i><a href="/facts/Nicotiana_tabacum/WQKhTHHK">Nicotiana tabacum</a></i> (Common tobacco) DB10 protein, amongst others.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> </p><p>In 2004, the first comprehensive protein-peptide interaction map for a human modular domain was reported using individually expressed WW domains and <a href="/facts/Genome/31Sm08JT">genome</a> predicted, PPxY-containing synthetic peptides.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> At present in the human <a href="/facts/Proteome/02gupgJW">proteome</a>, 98 WW domains<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> and more than 2000 PPxY-containing peptides,<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> have been identified from sequence analysis of the genome. </p> <h2 id="inhibitor">Inhibitor</h2> <p><a href="/facts/YAP1/jl4okjo9">YAP</a> is a WW domain-containing protein that functions as a potent <a href="/facts/Oncogene/WLFu6Ma5">oncogene</a>.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> Its WW domains must be intact for YAP to act as a transcriptional <a href="/facts/Co-activator/0lVABmQx">co-activator</a> that induces expression of proliferative genes.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> Recent study has shown that <a href="/facts/Endohedral_fullerene/4XnqTsxf">endohedral metallofullerenol</a>, a compound that was originally developed as a contrasting agent for MRI (<a href="/facts/Magnetic_resonance_imaging/Vh9yG9qq">magnetic resonance imaging</a>), has <a href="/facts/Antineoplastic/fWTLbaUT">antineoplastic</a> properties.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> Via <a href="/facts/Molecular_dynamics/yR3DNt6U">molecular dynamic simulations</a>, the ability of this compound to outcompete proline-rich peptides and bind effectively to the WW domain of YAP was documented.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> <a href="/facts/Endohedral_metallofullerenol/4XnqTsxf">Endohedral metallofullerenol</a> may represent a lead compound for the development of therapies for cancer patients who harbor amplified or overexpressed YAP.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a><a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> </p> <h2 id="in-the-study-of-protein-folding">In the study of protein folding</h2> <p>Because of its small size and well-defined structure, the WW domain was developed by the Gruebele and Kelly groups into a favorite subject of <a href="/facts/Protein_folding/rf3nR2Y1">protein folding</a> studies.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a><a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a><a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a><a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a><a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a><a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> Among these studies, the work of Rama Ranganathan<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a><a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> and <a href="/facts/David_E._Shaw/eDDsk8Th">David E. Shaw</a> are also notable.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a><a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> Ranganathan’s team has shown that a simple <a href="/facts/Statistical_potential/byN6XGXr">statistical energy function</a>, which identifies co-evolution between amino acid residues within the WW domain, is necessary and sufficient to specify sequence that folds into native structure.<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a> Using such an <a href="/facts/Algorithm/fnl5NmRt">algorithm</a>, he and his team synthesized libraries of artificial WW domains that functioned in a very similar manner to their natural counterparts, recognizing class-specific proline-rich ligand peptides,<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a> The Shaw laboratory developed a specialized machine that allowed elucidation of the atomic level behavior of the WW domain on a biologically relevant time scale.<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a> He and his team employed equilibrium simulations of a WW domain and identified seven unfolding and eight folding events.<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> </p><p>Being relatively short, 30 to 35 amino acids long, WW domain is amenable to chemical synthesis. It is cooperatively folded and can host chemically introduced non-canonical amino acids. Based on these properties, WW domain has been shown to be a versatile platform for the chemical interrogation of intramolecular interactions and conformational propensities in folded proteins.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> </p> <h2 id="external-links">External links</h2> <ul><li><a href="/facts/Eukaryotic_Linear_Motif_resource/MFaIocDu">Eukaryotic Linear Motif resource</a> motif class <a href="http://elm.eu.org/elms/elmPages/LIG_WW_1.html">LIG_WW_1</a></li> <li><a href="/facts/Eukaryotic_Linear_Motif_resource/MFaIocDu">Eukaryotic Linear Motif resource</a> motif class <a href="http://elm.eu.org/elms/elmPages/LIG_WW_2.html">LIG_WW_2</a></li> <li><a href="/facts/Eukaryotic_Linear_Motif_resource/MFaIocDu">Eukaryotic Linear Motif resource</a> motif class <a href="http://elm.eu.org/elms/elmPages/LIG_WW_3.html">LIG_WW_3</a></li></ul> This article incorporates text from the public domain <a href="/facts/Pfam/BKJa293w">Pfam</a> and <a href="/facts/InterPro/pKwNm8t7">InterPro</a>: <a href="https://www.ebi.ac.uk/interpro/entry/IPR001202">IPR001202</a> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Bork P, Sudol M (December 1994). "The WW domain: a signalling site in dystrophin?". Trends in Biochemical Sciences. 19 (12): 531–3. doi:10.1016/0968-0004(94)90053-1. PMID 7846762. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Hofmann K, Bucher P (January 1995). "The rsp5-domain is shared by proteins of diverse functions". FEBS Letters. 358 (2): 153–7. doi:10.1016/0014-5793(94)01415-W. PMID 7828727. S2CID 23110605. <a href="https://doi.org/10.1016%2F0014-5793%2894%2901415-W" target="_blank">https://doi.org/10.1016%2F0014-5793%2894%2901415-W</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>André B, Springael JY (December 1994). "WWP, a new amino acid motif present in single or multiple copies in various proteins including dystrophin and the SH3-binding Yes-associated protein YAP65". Biochemical and Biophysical Research Communications. 205 (2): 1201–5. doi:10.1006/bbrc.1994.2793. PMID 7802651. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Bork P, Sudol M (December 1994). "The WW domain: a signalling site in dystrophin?". Trends in Biochemical Sciences. 19 (12): 531–3. doi:10.1016/0968-0004(94)90053-1. PMID 7846762. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Hofmann K, Bucher P (January 1995). "The rsp5-domain is shared by proteins of diverse functions". FEBS Letters. 358 (2): 153–7. doi:10.1016/0014-5793(94)01415-W. PMID 7828727. S2CID 23110605. <a href="https://doi.org/10.1016%2F0014-5793%2894%2901415-W" target="_blank">https://doi.org/10.1016%2F0014-5793%2894%2901415-W</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>André B, Springael JY (December 1994). "WWP, a new amino acid motif present in single or multiple copies in various proteins including dystrophin and the SH3-binding Yes-associated protein YAP65". Biochemical and Biophysical Research Communications. 205 (2): 1201–5. doi:10.1006/bbrc.1994.2793. PMID 7802651. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Sudol M, Chen HI, Bougeret C, Einbond A, Bork P (August 1995). "Characterization of a novel protein-binding module--the WW domain". FEBS Letters. 369 (1): 67–71. doi:10.1016/0014-5793(95)00550-S. PMID 7641887. S2CID 20664267. <a href="https://doi.org/10.1016%2F0014-5793%2895%2900550-S" target="_blank">https://doi.org/10.1016%2F0014-5793%2895%2900550-S</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Chen HI, Sudol M (August 1995). "The WW domain of Yes-associated protein binds a proline-rich ligand that differs from the consensus established for Src homology 3-binding modules". Proceedings of the National Academy of Sciences of the United States of America. 92 (17): 7819–23. Bibcode:1995PNAS...92.7819C. doi:10.1073/pnas.92.17.7819. PMC 41237. PMID 7644498. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC41237" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC41237</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Chen HI, Sudol M (August 1995). "The WW domain of Yes-associated protein binds a proline-rich ligand that differs from the consensus established for Src homology 3-binding modules". Proceedings of the National Academy of Sciences of the United States of America. 92 (17): 7819–23. Bibcode:1995PNAS...92.7819C. doi:10.1073/pnas.92.17.7819. PMC 41237. PMID 7644498. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC41237" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC41237</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Bork P, Sudol M (December 1994). "The WW domain: a signalling site in dystrophin?". Trends in Biochemical Sciences. 19 (12): 531–3. doi:10.1016/0968-0004(94)90053-1. PMID 7846762. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Macias MJ, Hyvönen M, Baraldi E, Schultz J, Sudol M, Saraste M, Oschkinat H (August 1996). "Structure of the WW domain of a kinase-associated protein complexed with a proline-rich peptide". Nature. 382 (6592): 646–9. Bibcode:1996Natur.382..646M. doi:10.1038/382646a0. PMID 8757138. S2CID 4306964. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Bork P, Sudol M (December 1994). "The WW domain: a signalling site in dystrophin?". Trends in Biochemical Sciences. 19 (12): 531–3. doi:10.1016/0968-0004(94)90053-1. PMID 7846762. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Sudol M, Bork P, Einbond A, Kastury K, Druck T, Negrini M, Huebner K, Lehman D (June 1995). "Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain". The Journal of Biological Chemistry. 270 (24): 14733–41. doi:10.1074/jbc.270.24.14733. PMID 7782338. <a href="https://doi.org/10.1074%2Fjbc.270.24.14733" target="_blank">https://doi.org/10.1074%2Fjbc.270.24.14733</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Macias MJ, Hyvönen M, Baraldi E, Schultz J, Sudol M, Saraste M, Oschkinat H (August 1996). "Structure of the WW domain of a kinase-associated protein complexed with a proline-rich peptide". Nature. 382 (6592): 646–9. Bibcode:1996Natur.382..646M. doi:10.1038/382646a0. PMID 8757138. S2CID 4306964. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Chen HI, Sudol M (August 1995). "The WW domain of Yes-associated protein binds a proline-rich ligand that differs from the consensus established for Src homology 3-binding modules". Proceedings of the National Academy of Sciences of the United States of America. 92 (17): 7819–23. Bibcode:1995PNAS...92.7819C. doi:10.1073/pnas.92.17.7819. PMC 41237. PMID 7644498. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC41237" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC41237</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Macias MJ, Hyvönen M, Baraldi E, Schultz J, Sudol M, Saraste M, Oschkinat H (August 1996). "Structure of the WW domain of a kinase-associated protein complexed with a proline-rich peptide". Nature. 382 (6592): 646–9. Bibcode:1996Natur.382..646M. doi:10.1038/382646a0. PMID 8757138. S2CID 4306964. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Aragón E, Goerner N, Xi Q, Gomes T, Gao S, Massagué J, Macias MJ (October 2012). "Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-β Pathways". Structure. 20 (10): 1726–36. doi:10.1016/j.str.2012.07.014. PMC 3472128. PMID 22921829. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472128" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472128</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>Bruce MC, Kanelis V, Fouladkou F, Debonneville A, Staub O, Rotin D (October 2008). "Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain". The Biochemical Journal. 415 (1): 155–63. doi:10.1042/BJ20071708. PMID 18498246. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>Lu PJ, Zhou XZ, Shen M, Lu KP (February 1999). "Function of WW domains as phosphoserine- or phosphothreonine-binding modules". Science. 283 (5406): 1325–8. Bibcode:1999Sci...283.1325L. doi:10.1126/science.283.5406.1325. PMID 10037602. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></p></li> <li id="fn:20"><p>PDB: 1PIN; Ranganathan R, Lu KP, Hunter T, Noel JP (June 1997). "Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent". Cell. 89 (6): 875–86. doi:10.1016/S0092-8674(00)80273-1. PMID 9200606. S2CID 16219532. <a href="/wiki/Protein_Data_Bank" target="_blank">/wiki/Protein_Data_Bank</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></p></li> <li id="fn:21"><p>Verdecia MA, Bowman ME, Lu KP, Hunter T, Noel JP (August 2000). "Structural basis for phosphoserine-proline recognition by group IV WW domains". Nature Structural Biology. 7 (8): 639–43. doi:10.1038/77929. PMID 10932246. S2CID 20088089. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:21" class="footnote-back-ref">↩</a></p></li> <li id="fn:22"><p>Bedford MT, Sarbassova D, Xu J, Leder P, Yaffe MB (April 2000). "A novel pro-Arg motif recognized by WW domains". The Journal of Biological Chemistry. 275 (14): 10359–69. doi:10.1074/jbc.275.14.10359. PMID 10744724. <a href="https://doi.org/10.1074%2Fjbc.275.14.10359" target="_blank">https://doi.org/10.1074%2Fjbc.275.14.10359</a> <a href="#fnref:22" class="footnote-back-ref">↩</a></p></li> <li id="fn:23"><p>Ermekova KS, Zambrano N, Linn H, Minopoli G, Gertler F, Russo T, Sudol M (December 1997). "The WW domain of neural protein FE65 interacts with proline-rich motifs in Mena, the mammalian homolog of Drosophila enabled". The Journal of Biological Chemistry. 272 (52): 32869–77. doi:10.1074/jbc.272.52.32869. 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