Skip to main content
NCBI home page
Biophysical Journal logoLink to Biophysical Journal
. 2002 May;82(5):2720–2736. doi: 10.1016/S0006-3495(02)75613-0

Comparison of helix interactions in membrane and soluble alpha-bundle proteins.

Markus Eilers 1, Ashish B Patel 1, Wei Liu 1, Steven O Smith 1
PMCID: PMC1302060  PMID: 11964258

Abstract

Helix-helix interactions are important for the folding, stability, and function of membrane proteins. Here, two independent and complementary methods are used to investigate the nature and distribution of amino acids that mediate helix-helix interactions in membrane and soluble alpha-bundle proteins. The first method characterizes the packing density of individual amino acids in helical proteins based on the van der Waals surface area occluded by surrounding atoms. We have recently used this method to show that transmembrane helices pack more tightly, on average, than helices in soluble proteins. These studies are extended here to characterize the packing of interfacial and noninterfacial amino acids and the packing of amino acids in the interfaces of helices that have either right- or left-handed crossing angles, and either parallel or antiparallel orientations. We show that the most abundant tightly packed interfacial residues in membrane proteins are Gly, Ala, and Ser, and that helices with left-handed crossing angles are more tightly packed on average than helices with right-handed crossing angles. The second method used to characterize helix-helix interactions involves the use of helix contact plots. We find that helices in membrane proteins exhibit a broader distribution of interhelical contacts than helices in soluble proteins. Both helical membrane and soluble proteins make use of a general motif for helix interactions that relies mainly on four residues (Leu, Ala, Ile, Val) to mediate helix interactions in a fashion characteristic of left-handed helical coiled coils. However, a second motif for mediating helix interactions is revealed by the high occurrence and high average packing values of small and polar residues (Ala, Gly, Ser, Thr) in the helix interfaces of membrane proteins. Finally, we show that there is a strong linear correlation between the occurrence of residues in helix-helix interfaces and their packing values, and discuss these results with respect to membrane protein structure prediction and membrane protein stability.

Full Text

The Full Text of this article is available as a PDF (541.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adamian L., Liang J. Helix-helix packing and interfacial pairwise interactions of residues in membrane proteins. J Mol Biol. 2001 Aug 24;311(4):891–907. doi: 10.1006/jmbi.2001.4908. [DOI] [PubMed] [Google Scholar]
  2. Bowie J. U. Helix packing angle preferences. Nat Struct Biol. 1997 Nov;4(11):915–917. doi: 10.1038/nsb1197-915. [DOI] [PubMed] [Google Scholar]
  3. Bowie J. U. Helix packing in membrane proteins. J Mol Biol. 1997 Oct 10;272(5):780–789. doi: 10.1006/jmbi.1997.1279. [DOI] [PubMed] [Google Scholar]
  4. Chothia C., Levitt M., Richardson D. Helix to helix packing in proteins. J Mol Biol. 1981 Jan 5;145(1):215–250. doi: 10.1016/0022-2836(81)90341-7. [DOI] [PubMed] [Google Scholar]
  5. Chothia C., Levitt M., Richardson D. Structure of proteins: packing of alpha-helices and pleated sheets. Proc Natl Acad Sci U S A. 1977 Oct;74(10):4130–4134. doi: 10.1073/pnas.74.10.4130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chothia C. Structural invariants in protein folding. Nature. 1975 Mar 27;254(5498):304–308. doi: 10.1038/254304a0. [DOI] [PubMed] [Google Scholar]
  7. Cohen C., Parry D. A. Alpha-helical coiled coils and bundles: how to design an alpha-helical protein. Proteins. 1990;7(1):1–15. doi: 10.1002/prot.340070102. [DOI] [PubMed] [Google Scholar]
  8. DeDecker B. S., O'Brien R., Fleming P. J., Geiger J. H., Jackson S. P., Sigler P. B. The crystal structure of a hyperthermophilic archaeal TATA-box binding protein. J Mol Biol. 1996 Dec 20;264(5):1072–1084. doi: 10.1006/jmbi.1996.0697. [DOI] [PubMed] [Google Scholar]
  9. Efimov A. V. Packing of alpha-helices in globular proteins. Layer-structure of globin hydrophobic cores. J Mol Biol. 1979 Oct 15;134(1):23–40. doi: 10.1016/0022-2836(79)90412-1. [DOI] [PubMed] [Google Scholar]
  10. Eilers M., Shekar S. C., Shieh T., Smith S. O., Fleming P. J. Internal packing of helical membrane proteins. Proc Natl Acad Sci U S A. 2000 May 23;97(11):5796–5801. doi: 10.1073/pnas.97.11.5796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Eisenberg D., Schwarz E., Komaromy M., Wall R. Analysis of membrane and surface protein sequences with the hydrophobic moment plot. J Mol Biol. 1984 Oct 15;179(1):125–142. doi: 10.1016/0022-2836(84)90309-7. [DOI] [PubMed] [Google Scholar]
  12. Engelman D. M., Steitz T. A., Goldman A. Identifying nonpolar transbilayer helices in amino acid sequences of membrane proteins. Annu Rev Biophys Biophys Chem. 1986;15:321–353. doi: 10.1146/annurev.bb.15.060186.001541. [DOI] [PubMed] [Google Scholar]
  13. Engelman D. M., Zaccai G. Bacteriorhodopsin is an inside-out protein. Proc Natl Acad Sci U S A. 1980 Oct;77(10):5894–5898. doi: 10.1073/pnas.77.10.5894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fleming P. J., Richards F. M. Protein packing: dependence on protein size, secondary structure and amino acid composition. J Mol Biol. 2000 Jun 2;299(2):487–498. doi: 10.1006/jmbi.2000.3750. [DOI] [PubMed] [Google Scholar]
  15. Fu D., Libson A., Miercke L. J., Weitzman C., Nollert P., Krucinski J., Stroud R. M. Structure of a glycerol-conducting channel and the basis for its selectivity. Science. 2000 Oct 20;290(5491):481–486. doi: 10.1126/science.290.5491.481. [DOI] [PubMed] [Google Scholar]
  16. Gratkowski H., Lear J. D., DeGrado W. F. Polar side chains drive the association of model transmembrane peptides. Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):880–885. doi: 10.1073/pnas.98.3.880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gurezka R., Laage R., Brosig B., Langosch D. A heptad motif of leucine residues found in membrane proteins can drive self-assembly of artificial transmembrane segments. J Biol Chem. 1999 Apr 2;274(14):9265–9270. doi: 10.1074/jbc.274.14.9265. [DOI] [PubMed] [Google Scholar]
  18. Javadpour M. M., Eilers M., Groesbeek M., Smith S. O. Helix packing in polytopic membrane proteins: role of glycine in transmembrane helix association. Biophys J. 1999 Sep;77(3):1609–1618. doi: 10.1016/S0006-3495(99)77009-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Langosch D., Heringa J. Interaction of transmembrane helices by a knobs-into-holes packing characteristic of soluble coiled coils. Proteins. 1998 May 1;31(2):150–159. doi: 10.1002/(sici)1097-0134(19980501)31:2<150::aid-prot5>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  20. Lemmon M. A., Flanagan J. M., Treutlein H. R., Zhang J., Engelman D. M. Sequence specificity in the dimerization of transmembrane alpha-helices. Biochemistry. 1992 Dec 29;31(51):12719–12725. doi: 10.1021/bi00166a002. [DOI] [PubMed] [Google Scholar]
  21. Michie A. D., Orengo C. A., Thornton J. M. Analysis of domain structural class using an automated class assignment protocol. J Mol Biol. 1996 Sep 20;262(2):168–185. doi: 10.1006/jmbi.1996.0506. [DOI] [PubMed] [Google Scholar]
  22. Orengo C. A., Michie A. D., Jones S., Jones D. T., Swindells M. B., Thornton J. M. CATH--a hierarchic classification of protein domain structures. Structure. 1997 Aug 15;5(8):1093–1108. doi: 10.1016/s0969-2126(97)00260-8. [DOI] [PubMed] [Google Scholar]
  23. Pace C. N. Polar group burial contributes more to protein stability than nonpolar group burial. Biochemistry. 2001 Jan 16;40(2):310–313. doi: 10.1021/bi001574j. [DOI] [PubMed] [Google Scholar]
  24. Pattabiraman N., Ward K. B., Fleming P. J. Occluded molecular surface: analysis of protein packing. J Mol Recognit. 1995 Nov-Dec;8(6):334–344. doi: 10.1002/jmr.300080603. [DOI] [PubMed] [Google Scholar]
  25. Reddy B. V., Blundell T. L. Packing of secondary structural elements in proteins. Analysis and prediction of inter-helix distances. J Mol Biol. 1993 Oct 5;233(3):464–479. doi: 10.1006/jmbi.1993.1524. [DOI] [PubMed] [Google Scholar]
  26. Rees D. C., DeAntonio L., Eisenberg D. Hydrophobic organization of membrane proteins. Science. 1989 Aug 4;245(4917):510–513. doi: 10.1126/science.2667138. [DOI] [PubMed] [Google Scholar]
  27. Renthal R. Transmembrane and water-soluble helix bundles display reverse patterns of surface roughness. Biochem Biophys Res Commun. 1999 Oct 5;263(3):714–717. doi: 10.1006/bbrc.1999.1439. [DOI] [PubMed] [Google Scholar]
  28. Richards F. M., Kundrot C. E. Identification of structural motifs from protein coordinate data: secondary structure and first-level supersecondary structure. Proteins. 1988;3(2):71–84. doi: 10.1002/prot.340030202. [DOI] [PubMed] [Google Scholar]
  29. Richards F. M., Lim W. A. An analysis of packing in the protein folding problem. Q Rev Biophys. 1993 Nov;26(4):423–498. doi: 10.1017/s0033583500002845. [DOI] [PubMed] [Google Scholar]
  30. Richards F. M. Protein stability: still an unsolved problem. Cell Mol Life Sci. 1997 Oct;53(10):790–802. doi: 10.1007/s000180050100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Richmond T. J., Richards F. M. Packing of alpha-helices: geometrical constraints and contact areas. J Mol Biol. 1978 Mar 15;119(4):537–555. doi: 10.1016/0022-2836(78)90201-2. [DOI] [PubMed] [Google Scholar]
  32. Russ W. P., Engelman D. M. TOXCAT: a measure of transmembrane helix association in a biological membrane. Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):863–868. doi: 10.1073/pnas.96.3.863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Russ W. P., Engelman D. M. The GxxxG motif: a framework for transmembrane helix-helix association. J Mol Biol. 2000 Feb 25;296(3):911–919. doi: 10.1006/jmbi.1999.3489. [DOI] [PubMed] [Google Scholar]
  34. Senes A., Gerstein M., Engelman D. M. Statistical analysis of amino acid patterns in transmembrane helices: the GxxxG motif occurs frequently and in association with beta-branched residues at neighboring positions. J Mol Biol. 2000 Feb 25;296(3):921–936. doi: 10.1006/jmbi.1999.3488. [DOI] [PubMed] [Google Scholar]
  35. Senes A., Ubarretxena-Belandia I., Engelman D. M. The Calpha ---H...O hydrogen bond: a determinant of stability and specificity in transmembrane helix interactions. Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9056–9061. doi: 10.1073/pnas.161280798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Smith S. O., Song D., Shekar S., Groesbeek M., Ziliox M., Aimoto S. Structure of the transmembrane dimer interface of glycophorin A in membrane bilayers. Biochemistry. 2001 Jun 5;40(22):6553–6558. doi: 10.1021/bi010357v. [DOI] [PubMed] [Google Scholar]
  37. Stevens T. J., Arkin I. T. Are membrane proteins "inside-out" proteins? Proteins. 1999 Jul 1;36(1):135–143. doi: 10.1002/(sici)1097-0134(19990701)36:1<135::aid-prot11>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  38. Ulmschneider M. B., Sansom M. S. Amino acid distributions in integral membrane protein structures. Biochim Biophys Acta. 2001 May 2;1512(1):1–14. doi: 10.1016/s0005-2736(01)00299-1. [DOI] [PubMed] [Google Scholar]
  39. Walther D., Eisenhaber F., Argos P. Principles of helix-helix packing in proteins: the helical lattice superposition model. J Mol Biol. 1996 Jan 26;255(3):536–553. doi: 10.1006/jmbi.1996.0044. [DOI] [PubMed] [Google Scholar]
  40. Walther D., Springer C., Cohen F. E. Helix-helix packing angle preferences for finite helix axes. Proteins. 1998 Dec 1;33(4):457–459. [PubMed] [Google Scholar]
  41. Zhou F. X., Merianos H. J., Brunger A. T., Engelman D. M. Polar residues drive association of polyleucine transmembrane helices. Proc Natl Acad Sci U S A. 2001 Feb 13;98(5):2250–2255. doi: 10.1073/pnas.041593698. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES