Ubiquitin chains

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Ubiquitin chains (or polyubiquitin chains) are protein post-translational modifications that regulate proteasome dependent protein degradation, the cellular response to DNA damage, the inflammatory response and other cellular functions [1][2]. Chains begin as a single ubiquitin attached to the modified protein via an isopeptide linkage between a lysine side chain within the substrate protein and the C-terminal glycine of ubiquitin. The chain is built and extended by ubiquitination of ubiquitin on one of the lysines of ubiquitin or the N-terminus. There are a total of seven lysines in ubiquitin (K6, K11, K27, K29, K33, K48, and K63) and chains using all seven lysines have been identified [3]. Chains are frequently referred to in the literature by the lysine position in ubiquitin that connects one ubiquitin to the next. For example, chains built on lysine 48 of ubiquitin are called K48-linked chains. N-terminal to C-terminal connection of ubiquitin molecules is called a linear ubiquitin chain and chains which contain linkages through several lysine positions are called mixed chains [4]. Ubiquitin chains with different linkages can have different cellular functions some of which are summarized below. The basis for the functional differences between polyubiquitin chains of different linkages were not apparent until the X-ray and NMR structures of several chains were solved.



Contents

K48-linked ubiquitin chains

K48-linked tetraubiquitin, 2o6v

Drag the structure with the mouse to rotate

K48-linked ubiquitin chains are the primary signal for proteasome dependent degradation of proteins. The attachment of a chain of four or more ubiquitin molecules to a protein is required for efficient degradation. The X-ray crystal structure of K-48 linked diubiquitin[5] showed inter-ubiquitin interactions between the (residues L8, I44, V70) of the two molecules. A later X-ray crystal structure of K48-linked tetraubiquitin[6] showed that the ubiquitin chain adopted a globular tertiary structure which has been described as a . The interactions between the hydrophobic patches of ubiquitin molecules in 1 and 2 or 3 and 4 were similar to those observed in the diubiquitin structure [5]. Since the initial structure, several K48-linked tetraubiquitin crystal structures [7] [8] [9] have shown there are slight rearrangements of the tertiary structure of the chain dependent upon the pH of the crystallization solution. At pH 6.7, the chain adopts what is known as the closed conformation, because the chain remains in a largely compact form. At pH values less than 4.5, the interaction between diubiquitin molecules becomes weaker and the chain is less compact and there are fewer inter-ubiquitin contacts [8]. The different tertiary conformations of the polyubiquitin chain are thought to be indicative of the dynamics of the K48-linked ubiquitin chain in the cell. These changes would allow ubiquitin binding proteins to interact with the hydrophobic patches of the ubiquitin molecules[10]. The structure of cyclic K48-linked tetraubiquitin adopts the same dimer of ubiquitin dimer structure seen in the linear chains [11]. The authors of this structure suggest this structure demonstrates the inherent flexibility of the ubiquitin chain.




K63-linked ubiquitin chains

Structure of K63-linked tetraubiquitin in hte fully extended conformation, 3hm3.

Drag the structure with the mouse to rotate

K63-linked ubiquitin chains bound to proteins are associated with the DNA damage response and NF-κB signaling [12]. In contrast to K48-linked tetraubiquitin, the structure of K63-linked ubiquitin is linear, with no inter-ubiquitin contacts apparent in the crystal [13][14]. Small angle X-ray scattering of K63-linked tetraubiquitin confirmed the observations from crystal structures but suggested that a small percentage of chains adopted a partially compacted structure [13]. The specific inter-ubiquitin contacts were not apparent from this experiment. The K63-linked ubiquitin chain binding domains in the signaling proteins NEMO [15] and Rap80 [16] bridge the hydrophobic patches of consecutive ubiquitins in the chain through a single alpha helix. The work of Sims and coworkers [17] showed that decreasing the distance between the ubiquitin interacting motifs in Rap80 decreased the affinity of the Rap80 binding domain for the ubiquitin chain.









K11-linked ubiquitin chains

K11-linked ubiquitin chains are linked to proteasomal degradation and possibly endoplasmic reticulum associated degradation [3]. The X-ray crystal structure of K11-linked chains shows a compact structure like K48-linked ubiquitin chains [18]. However, the hydrophobic patches which mediate the inter-ubiquitin interactions in K48-linked chains are surface exposed in K11-linked chains. The interaction surface between the two ubiquitins consists of a number of charged and hydrogen bond forming residues. NMR or crystal structures of longer K11-linked chains have not been published to confirm whether this conformation persists with additional ubiquitins.


Linear ubiquitin chains

Linear ubiquitin chains are linked by a peptide bond between the N-terminal alpha-amino group of one ubiquitin and the C-terminus of another ubiquitin. These chains are associated with NF-κB signaling [19] and some cellular ubiquitin is expressed as linear chains of ubiquitin before processing to monoubiquitin by ubiquitin proteases [20]. Structurally, linear ubiquitin chains are similar to the extended conformation observed for K63-linked chains [21].


Ubiquitin chains of other linkages

As of June 2011, there are not structures available for ubiquitin chains with K6, K27, K29, or K33 linkages. Molecular modeling by Fushman and Walker [22] suggest K6 and K27 linked chains will adopt a compact structure similar to that of K48-linked chains, while K29 and K33-linked chains will adopt a more open conformation. The model of K11-linked chains in this study suggests inter-ubiquitin contact between the hydrophobic patches [22], while the crystal structure suggests these patches are not interacting [18]. This discrepancy may be because burial of the hydrophobic patch was a restraint in the modeling. Further structural and biochemical work is necessary to determine the correct conformation.


Chains of Ubiquitin-like proteins (Ubls)

Structure of a ISG15 monomer. The tertiary structure consists of two ubiquitin-like folds, resembling a molecule of diubiquitin.

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SUMO (Small Ubiquitin-like Modifying Object) does form chains[23], however no structural information on these chains is available. Chains of other Ubls may exist, but there is not significant data on their structure and function. The tertiary structure of ISG15 is comprised of two beta grasp folds and is similar in appearance to diubiquitin [24]. Whether this influences the function of ISG15 is not clear at this time.














References

  1. ↑ Chen ZJ, Sun LJ. Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell. 2009 Feb 13;33(3):275-86. PMID:19217402 doi:10.1016/j.molcel.2009.01.014
  2. ↑ Pickart CM. Targeting of substrates to the 26S proteasome. FASEB J. 1997 Nov;11(13):1055-66. PMID:9367341
  3. ↑ 3.0 3.1 Xu P, Duong DM, Seyfried NT, Cheng D, Xie Y, Robert J, Rush J, Hochstrasser M, Finley D, Peng J. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell. 2009 Apr 3;137(1):133-45. PMID:19345192 doi:10.1016/j.cell.2009.01.041
  4. ↑ Ikeda F, Dikic I. Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series. EMBO Rep. 2008 Jun;9(6):536-42. PMID:18516089 doi:10.1038/embor.2008.93
  5. ↑ 5.0 5.1 Cook WJ, Jeffrey LC, Carson M, Chen Z, Pickart CM. Structure of a diubiquitin conjugate and a model for interaction with ubiquitin conjugating enzyme (E2). J Biol Chem. 1992 Aug 15;267(23):16467-71. PMID:1322903
  6. ↑ Cook WJ, Jeffrey LC, Kasperek E, Pickart CM. Structure of tetraubiquitin shows how multiubiquitin chains can be formed. J Mol Biol. 1994 Feb 18;236(2):601-9. PMID:8107144 doi:http://dx.doi.org/10.1006/jmbi.1994.1169
  7. ↑ Phillips CL, Thrower J, Pickart CM, Hill CP. Structure of a new crystal form of tetraubiquitin. Acta Crystallogr D Biol Crystallogr. 2001 Feb;57(Pt 2):341-4. PMID:11173499
  8. ↑ 8.0 8.1 Eddins MJ, Varadan R, Fushman D, Pickart CM, Wolberger C. Crystal structure and solution NMR studies of Lys48-linked tetraubiquitin at neutral pH. J Mol Biol. 2007 Mar 16;367(1):204-11. Epub 2006 Dec 29. PMID:17240395 doi:10.1016/j.jmb.2006.12.065
  9. ↑ Trempe JF, Brown NR, Noble ME, Endicott JA. A new crystal form of Lys48-linked diubiquitin. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Sep 1;66(Pt, 9):994-8. Epub 2010 Aug 21. PMID:20823512 doi:10.1107/S1744309110027600
  10. ↑ Beal RE, Toscano-Cantaffa D, Young P, Rechsteiner M, Pickart CM. The hydrophobic effect contributes to polyubiquitin chain recognition. Biochemistry. 1998 Mar 3;37(9):2925-34. PMID:9485444 doi:10.1021/bi972514p
  11. ↑ Satoh T, Sakata E, Yamamoto S, Yamaguchi Y, Sumiyoshi A, Wakatsuki S, Kato K. Crystal structure of cyclic Lys48-linked tetraubiquitin. Biochem Biophys Res Commun. 2010 Aug 19. PMID:20728431 doi:10.1016/j.bbrc.2010.08.057
  12. ↑ Hadian K, Griesbach RA, Dornauer S, Wanger TM, Nagel D, Metlitzky M, Beisker W, Schmidt-Supprian M, Krappmann D. NF-{kappa}B Essential Modulator (NEMO) Interaction with Linear and Lys-63 Ubiquitin Chains Contributes to NF-{kappa}B Activation. J Biol Chem. 2011 Jul 22;286(29):26107-17. Epub 2011 May 26. PMID:21622571 doi:10.1074/jbc.M111.233163
  13. ↑ 13.0 13.1 Datta AB, Hura GL, Wolberger C. The structure and conformation of Lys63-linked tetraubiquitin. J Mol Biol. 2009 Oct 9;392(5):1117-24. Epub 2009 Aug 4. PMID:19664638 doi:10.1016/j.jmb.2009.07.090
  14. ↑ Weeks SD, Grasty KC, Hernandez-Cuebas L, Loll PJ. Crystal structures of Lys-63-linked tri- and di-ubiquitin reveal a highly extended chain architecture. Proteins. 2009 Aug 12. PMID:19731378 doi:10.1002/prot.22568
  15. ↑ Yoshikawa A, Sato Y, Yamashita M, Mimura H, Yamagata A, Fukai S. Crystal structure of the NEMO ubiquitin-binding domain in complex with Lys 63-linked di-ubiquitin. FEBS Lett. 2009 Oct 20;583(20):3317-22. Epub 2009 Sep 18. PMID:19766637 doi:10.1016/j.febslet.2009.09.028
  16. ↑ Sato Y, Yoshikawa A, Mimura H, Yamashita M, Yamagata A, Fukai S. Structural basis for specific recognition of Lys 63-linked polyubiquitin chains by tandem UIMs of RAP80. EMBO J. 2009 Aug 19;28(16):2461-8. Epub 2009 Jun 18. PMID:19536136 doi:10.1038/emboj.2009.160
  17. ↑ Sims JJ, Cohen RE. Linkage-specific avidity defines the lysine 63-linked polyubiquitin-binding preference of rap80. Mol Cell. 2009 Mar 27;33(6):775-83. PMID:19328070 doi:S1097-2765(09)00125-7
  18. ↑ 18.0 18.1 Bremm A, Freund SM, Komander D. Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne. Nat Struct Mol Biol. 2010 Aug;17(8):939-47. Epub 2010 Jul 11. PMID:20622874 doi:10.1038/nsmb.1873
  19. ↑ Rahighi S, Ikeda F, Kawasaki M, Akutsu M, Suzuki N, Kato R, Kensche T, Uejima T, Bloor S, Komander D, Randow F, Wakatsuki S, Dikic I. Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell. 2009 Mar 20;136(6):1098-109. PMID:19303852 doi:10.1016/j.cell.2009.03.007
  20. ↑ Sharp PM, Li WH. Ubiquitin genes as a paradigm of concerted evolution of tandem repeats. J Mol Evol. 1987;25(1):58-64. PMID:3041010
  21. ↑ Komander D, Reyes-Turcu F, Licchesi JD, Odenwaelder P, Wilkinson KD, Barford D. Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains. EMBO Rep. 2009 May;10(5):466-73. Epub 2009 Apr 17. PMID:19373254 doi:10.1038/embor.2009.55
  22. ↑ 22.0 22.1 Fushman D, Walker O. Exploring the Linkage Dependence of Polyubiquitin Conformations Using Molecular Modeling. J Mol Biol. 2010 Jan 29;395(4):803-814. Epub 2009 Oct 22. PMID:19853612 doi:S0022-2836(09)01279-0
  23. ↑ Tatham MH, Jaffray E, Vaughan OA, Desterro JM, Botting CH, Naismith JH, Hay RT. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem. 2001 Sep 21;276(38):35368-74. Epub 2001 Jul 12. PMID:11451954 doi:10.1074/jbc.M104214200
  24. ↑ Narasimhan J, Wang M, Fu Z, Klein JM, Haas AL, Kim JJ. Crystal structure of the interferon-induced ubiquitin-like protein ISG15. J Biol Chem. 2005 Jul 22;280(29):27356-65. Epub 2005 May 24. PMID:15917233 doi:10.1074/jbc.M502814200


--Christopher Berndsen 16:00, 2 August 2011 (IDT)

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