Omega loop

The omega loop[1][2] is a non-regular protein structural motif, consisting of a loop of six or more amino acid residues and any amino acid sequence. The defining characteristic is that residues that make up the beginning and end of the loop are close together in space with no intervening lengths of regular secondary structural motifs. It is named after its shape, which resembles the upper-case Greek letter Omega (Ω).

Structure

Omega loops, being non-regular, non-repeating secondary structural units, have a variety of three-dimensional shapes. Omega loop shapes are analyzed to identify recurring patterns in dihedral angles and overall loop shape to help identify potential roles in protein folding and function.[3][4]

Since loops are almost always at the protein surface, it is often assumed that these structures are flexible; however, different omega loops exhibit ranges of flexibility across different time scales of protein motion and have been identified as playing a role in the folding of some proteins, including HIV-1 reverse transcriptase;[5][6] cytochrome c;[7][8] and nucleases.[9][10]

Function

Omega loops can contribute to protein function. For example, omega loops can help stabilize interactions between protein and ligand, such as in the enzyme triose phosphate isomerase,[11] and can directly affect protein function in other enzymes.[12][13] A heritable coagulation disorder is caused by a single-site mutation in an omega loop of protein C.[14]

Likewise, omega loops play an interesting role in the function of the beta-lactamases: mutations in the "omega loop region" of a beta-lactamase can change its specific function and substrate profile,[15][16][17] perhaps due to an important functional role of the correlated dynamics of the region.[18]

Cytochrome c

Omega loops have long been recognized also for their importance in the function and folding of the protein cytochrome c, contributing both key functional residues and well as important dynamic properties.[19][20][21] Many researchers have studied omega loop function and dynamics in specific protein systems using a so-called "loop swap" approach, in which loops are swapped between (usually) homologous proteins.[22][23][24]

References

  1. ↑ Leszczynski, JF; Rose, GD (14 Nov 1986). "Loops in globular proteins: a novel category of secondary structure". Science 234 (4778): 849–855. doi:10.1126/science.3775366. PMID 3775366.
  2. ↑ Fetrow, JS (June 1995). "Omega loops: nonregular secondary structures significant in protein function and stability". FASEB J 9 (9): 708–17. PMID 7601335.
  3. ↑ Pal, M; Dasgupta, S (1 Jun 2003). "The nature of the turn in omega loops of proteins". Proteins 51 (4): 591–606. doi:10.1002/prot.10376. PMID 12784218.
  4. ↑ Dhar, J; Chakrabarti, P (Jun 2015). "Defining the loop structures in proteins based on composite β-turn mimics". Protein Eng Des Sel 28 (6): 153–61. doi:10.1093/protein/gzv017. PMID 25870305.
  5. ↑ Mager, PP (Dec 1996). "Molecular simulation of the folding patterns of the omega-loop (Tyr181 to Tyr188) of HIV-1 reverse transcriptase". Drug Des Discov 14 (3): 213–23. PMID 9017364.
  6. ↑ Mager, PP; Walther, H (Dec 1996). "A hydrophilic omega-loop (Tyr181 to Tyr188) in the nonsubstrate binding area of HIV-1 reverse transcriptase". Drug Des Discov 14 (3): 225–39. PMID 9017365.
  7. ↑ Maity, H; Rumbley, JN; Englander, SW (1 May 2006). "Functional role of a protein foldon--an Omega-loop foldon controls the alkaline transition in ferricytochrome c". Proteins 63 (2): 349–55. doi:10.1002/prot.20757. PMID 16287119.
  8. ↑ Caroppi, P; Sinibaldi, F; Santoni, E; Howes, BD; Fiorucci, L; Ferri, T; Ascoli, F; Smulevich, G; Santucci, R (Dec 2004). "The 40s Omega-loop plays a critical role in the stability and the alkaline conformational transition of cytochrome c". J Biol Inorg Chem 9 (8): 997–1006. doi:10.1007/s00775-004-0601-9. PMID 15503233.
  9. ↑ Vu, ND; Feng, H; Bai, Y (30 Mar 2004). "The folding pathway of barnase: the rate-limiting transition state and a hidden intermediate under native conditions". Biochemistry 43 (12): 3346–56. doi:10.1021/bi0362267. PMID 15035606.
  10. ↑ Wang, X; Wang, M; Tong, Y; Shan, L; Wang, J (Oct 2006). "Probing the folding capacity and residual structures in 1-79 residues fragment of staphylococcal nuclease by biophysical and NMR methods". Biochimie 88 (10): 1343–55. doi:10.1016/j.biochi.2006.05.002. PMID 17045725.
  11. ↑ Xiang, J; Jung, JY; Sampson, NS (14 Sep 2004). "Entropy effects on protein hinges: the reaction catalyzed by triosephosphate isomerase". Biochemistry 43 (36): 11436–45. doi:10.1021/bi049208d. PMID 15350130.
  12. ↑ Neuhaus, FC (Sep 2011). "Role of the omega loop in specificity determination in subsite 2 of the D-alanine:D-alanine (D-lactate) ligase from Leuconostoc mesenteroides: a molecular docking study". J Mol Graph Model 30: 31–7. doi:10.1016/j.jmgm.2011.06.002. PMID 21727015.
  13. ↑ Sampson, NS; Kass, IJ; Ghoshroy, KB (21 Apr 1998). "Assessment of the role of an omega loop of cholesterol oxidase: a truncated loop mutant has altered substrate specificity". Biochemistry 37 (16): 5770–8. doi:10.1021/bi973067g. PMID 9548964.
  14. ↑ Preston, RJ; Morse, C; Murden, SL; Brady, SK; O'Donnell, JS; Mumford, AD (Mar 2009). "The protein C omega-loop substitution Asn2Ile is associated with reduced protein C anticoagulant activity". Br J Haematol 144 (6): 946–53. doi:10.1111/j.1365-2141.2008.07550.x. PMID 19133979.
  15. ↑ Levitt, PS; Papp-Wallace, KM; Taracila, MA; Hujer, AM; Winkler, ML; Smith, KM; Xu, Y; Harris, ME; Bonomo, RA (14 Sep 2013). "Exploring the role of a conserved class A residue in the Ω-Loop of KPC-2 β-lactamase: a mechanism for ceftazidime hydrolysis". J Biol Chem 287 (38): 31783–93. doi:10.1074/jbc.M112.348540. PMC 3442512. PMID 22843686.
  16. ↑ Stojanoski, V; Chow, DC; Hu, L; Sankaran, B; Gilbert, HF; Prasad, BV; Palzkill, T (17 Apr 2015). "A triple mutant in the Ω-loop of TEM-1 β-lactamase changes the substrate profile via a large conformational change and an altered general base for catalysis". J Biol Chem 290 (16): 10382–94. doi:10.1074/jbc.M114.633438. PMID 25713062.
  17. ↑ Dutta, M; Kar, D; Bansal, A; Chakraborty, S; Ghosh, AS (Apr 2015). "A single amino acid substitution in the Ω-like loop of E. coli PBP5 disrupts its ability to maintain cell shape and intrinsic beta-lactam resistance". Microbiology 161 (Pt 4): 895–902. doi:10.1099/mic.0.000052. PMID 25667006.
  18. ↑ Brown, JR; Livesay, DR (27 May 2015). "Flexibility Correlation between Active Site Regions Is Conserved across Four AmpC β-Lactamase Enzymes". PLOS ONE 10 (5): e0125832. doi:10.1371/journal.pone.0125832. PMC 4446314. PMID 26018804.
  19. ↑ McClelland, LJ; Seagraves, SM; Khan, MK; Cherney, MM; Bandi, S; Culbertson, JE; Bowler, BE (Jul 2015). "The response of Ω-loop D dynamics to truncation of trimethyllysine 72 of yeast iso-1-cytochrome c depends on the nature of loop deformation". J Biol Inorg Chem 20 (5): 805–19. doi:10.1007/s00775-015-1267-1. PMID 25948392.
  20. ↑ Krishna, MM; Lin, Y; Rumbley, JN; Englander, SW (1 Aug 2003). "Cooperative omega loops in cytochrome c: role in folding and function". J Mol Biol 331 (1): 29–36. doi:10.1016/s0022-2836(03)00697-1. PMID 12875833.
  21. ↑ Fetrow, JS; Dreher, U; Wiland, DJ; Schaak, DL; Boose, TL (Apr 1998). "Mutagenesis of histidine 26 demonstrates the importance of loop-loop and loop-protein interactions for the function of iso-1-cytochrome c". Protein Sci 7 (4): 994–1005. doi:10.1002/pro.5560070417. PMC 2143970. PMID 9568906.
  22. ↑ Takehara, S; Onda, M; Zhang, J; Nishiyama, M; Yang, X; Mikami, B; Lomas, DA (24 Apr 2009). "The 2.1-A crystal structure of native neuroserpin reveals unique structural elements that contribute to conformational instability". J Mol Biol 388 (1): 11–20. doi:10.1016/j.jmb.2009.03.007. PMID 19285087.
  23. ↑ Murphy, ME; Fetrow, JS; Burton, RE; Brayer, GD (Sep 1993). "The structure and function of omega loop A replacements in cytochrome c". Protein Sci 2 (9): 1429–40. doi:10.1002/pro.5560020907. PMC 2142463. PMID 8401228.
  24. ↑ Fetrow, JS; Cardillo, TS; Sherman, F (1989). "Deletions and replacements of omega loops in yeast iso-1-cytochrome c". Proteins 6 (4): 372–81. doi:10.1002/prot.340060404. PMID 2560195.


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