Omega loop explained

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]

Notes and References

  1. Leszczynski. JF. Rose. GD. Loops in globular proteins: a novel category of secondary structure. Science. 14 Nov 1986. 234. 4778. 849–855. 10.1126/science.3775366. 3775366. 1986Sci...234..849L.
  2. Fetrow. JS. Omega loops: nonregular secondary structures significant in protein function and stability. FASEB J. June 1995. 9. 9. 708–17. 7601335. 10.1096/fasebj.9.9.7601335. free . 23775489.
  3. Pal. M. Dasgupta. S. The nature of the turn in omega loops of proteins. Proteins. 1 Jun 2003. 51. 4. 591–606. 12784218. 10.1002/prot.10376. 44815936.
  4. Dhar. J. Chakrabarti. P. Defining the loop structures in proteins based on composite β-turn mimics. Protein Eng Des Sel. Jun 2015. 28. 6. 153–61. 10.1093/protein/gzv017. 25870305. free.
  5. Mager. PP. Molecular simulation of the folding patterns of the omega-loop (Tyr181 to Tyr188) of HIV-1 reverse transcriptase. Drug des Discov. Dec 1996. 14. 3. 213–23. 9017364.
  6. Mager. PP. Walther. H. A hydrophilic omega-loop (Tyr181 to Tyr188) in the nonsubstrate binding area of HIV-1 reverse transcriptase. Drug des Discov. Dec 1996. 14. 3. 225–39. 9017365.
  7. Maity. H. Rumbley. JN. Englander. SW. Functional role of a protein foldon--an Omega-loop foldon controls the alkaline transition in ferricytochrome c. Proteins. 1 May 2006. 63. 2. 349–55. 16287119. 10.1002/prot.20757. 10.1.1.596.3784. 38183696.
  8. Caroppi. P. Sinibaldi. F. Santoni. E. Howes. BD. Fiorucci. L. Ferri. T. Ascoli. F. Smulevich. G. Santucci. R. The 40s Omega-loop plays a critical role in the stability and the alkaline conformational transition of cytochrome c. J Biol Inorg Chem. Dec 2004. 9. 8. 997–1006. 15503233. 10.1007/s00775-004-0601-9. 2108/34631. 2130725. free.
  9. Vu. ND. Feng. H. Bai. Y. The folding pathway of barnase: the rate-limiting transition state and a hidden intermediate under native conditions. 30 Mar 2004. Biochemistry. 43. 12. 3346–56. 15035606. 10.1021/bi0362267.
  10. Wang. X. Wang. M. Tong. Y. Shan. L. Wang. J. Probing the folding capacity and residual structures in 1-79 residues fragment of staphylococcal nuclease by biophysical and NMR methods. Biochimie. Oct 2006. 88. 10. 1343–55. 17045725. 10.1016/j.biochi.2006.05.002.
  11. Xiang. J. Jung. JY. Sampson. NS. Entropy effects on protein hinges: the reaction catalyzed by triosephosphate isomerase. Biochemistry. 14 Sep 2004. 43. 36. 11436–45. 10.1021/bi049208d. 15350130.
  12. Neuhaus. FC. 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. Sep 2011. 30. 31–7. 10.1016/j.jmgm.2011.06.002. 21727015.
  13. Sampson. NS. Kass. IJ. Ghoshroy. KB. Assessment of the role of an omega loop of cholesterol oxidase: a truncated loop mutant has altered substrate specificity. Biochemistry. 21 Apr 1998. 37. 16. 5770–8. 9548964. 10.1021/bi973067g.
  14. Preston. RJ. Morse. C. Murden. SL. Brady. SK. O'Donnell. JS. Mumford. AD. The protein C omega-loop substitution Asn2Ile is associated with reduced protein C anticoagulant activity. Br J Haematol. Mar 2009. 144. 6. 946–53. 10.1111/j.1365-2141.2008.07550.x. 19133979. 1618500.
  15. Levitt. PS. Papp-Wallace. KM. Taracila. MA. Hujer. AM. Winkler. ML. Smith. KM. Xu. Y. Harris. ME. Bonomo. RA. 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. 14 Sep 2013. 287. 38. 31783–93. 10.1074/jbc.M112.348540. 22843686. 3442512. free.
  16. Stojanoski. V. Chow. DC. Hu. L. Sankaran. B. Gilbert. HF. Prasad. BV. Palzkill. T. 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. 17 Apr 2015. 290. 16. 10382–94. 10.1074/jbc.M114.633438. 25713062. 4400348. free.
  17. Dutta. M. Kar. D. Bansal. A. Chakraborty. S. Ghosh. AS. 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. Apr 2015. 161. Pt 4. 895–902. 10.1099/mic.0.000052. 25667006. free.
  18. Brown. JR. Livesay. DR. Flexibility Correlation between Active Site Regions Is Conserved across Four AmpC β-Lactamase Enzymes. PLOS ONE. 27 May 2015. 10. 5. e0125832. 10.1371/journal.pone.0125832. 26018804. 4446314. 2015PLoSO..1025832B. free.
  19. McClelland. LJ. Seagraves. SM. Khan. MK. Cherney. MM. Bandi. S. Culbertson. JE. Bowler. BE. 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. Jul 2015. 20. 5. 805–19. 10.1007/s00775-015-1267-1. 25948392. 4485566.
  20. Krishna. MM. Lin. Y. Rumbley. JN. Englander. SW. Cooperative omega loops in cytochrome c: role in folding and function. J Mol Biol. 1 Aug 2003. 331. 1. 29–36. 12875833. 10.1016/s0022-2836(03)00697-1.
  21. Fetrow. JS. Dreher. U. Wiland. DJ. Schaak. DL. Boose. TL. Mutagenesis of histidine 26 demonstrates the importance of loop-loop and loop-protein interactions for the function of iso-1-cytochrome c. Protein Sci. Apr 1998. 7. 4. 994–1005. 9568906. 10.1002/pro.5560070417. 2143970.
  22. Takehara. S. Onda. M. Zhang. J. Nishiyama. M. Yang. X. Mikami. B. Lomas. DA. The 2.1-A crystal structure of native neuroserpin reveals unique structural elements that contribute to conformational instability. 24 Apr 2009. J Mol Biol. 388. 1. 11–20. 10.1016/j.jmb.2009.03.007. 19285087.
  23. Murphy. ME. Fetrow. JS. Burton. RE. Brayer. GD. The structure and function of omega loop A replacements in cytochrome c. Protein Sci. Sep 1993. 2. 9. 1429–40. 8401228. 10.1002/pro.5560020907. 2142463.
  24. Fetrow. JS. Cardillo. TS. Sherman. F. Deletions and replacements of omega loops in yeast iso-1-cytochrome c. Proteins. 1989. 6. 4. 372–81. 2560195. 10.1002/prot.340060404. 25525703.

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