Computational Structural Analysis of C-Terminal Residues of Proteins Containing Transmembrane Regions

RishyaKulya MC, Saravanan KM


For the past few years, the numbers of transmembrane protein structures in Protein Data Bank have been increased substantially. It is of interest to analyze the terminal residues of transmembrane proteins by using computational approaches. Also, up to our knowledge, no analysis was reported in the literature on the study of terminal residues in transmembrane proteins. While the N-terminal position of alpha and beta transmembrane proteins are composed of signal peptides, in the present work, a careful, in-depth, computational analysis such as residue preference, stability upon mutation, solvent accessibility, hydrogen bonding and carboxy terminal pentapeptide pattern search respectively has been done on C-terminal residues. Alanine in alpha transmembrane proteins and phenylalanine in beta transmembrane proteins are highly preferred. Glutamic acid and glycine residues can be substituted at the terminal sites of alpha and beta transmembrane proteins without affecting the protein's overall stability. Hydrogen bonding of terminal residues is studied in detail. Pattern search of carboxy pentapeptides shows that identical pentapeptides with reference to the position can adopt a different secondary structure. The results discussed in this paper may help to understand the role of carboxy terminal residues in alpha and beta transmembrane proteins. From our analysis, we insist that the preferences and structural analysis of carboxy terminal residues in alpha and beta transmembrane proteins, can help to model and design novel transmembrane proteins.


C-terminal residues; protein stability; Hydrogen bonding; Protein-protein interactions; Protein folding.

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Thornton JM, Sibanda BL., Amino and carboxy-terminal regions in globular proteins, J Mol Biol, 1983; 167: 443-60.

Takano K, Tsuchimori K, Yamagata , Yutani K., Effect of foreign N-terminal residues on the conformational stability of human lysozyme, Eur J Biochem, 1999; 266: 675-82.

Kaufmann E, Klaus W, Norbert G., Intermediate filament forming ability of desmin derivatives lacking either the amino-terminal 67 or the carboxy-terminal 27 residues, J Mol Biol, 1985; 185: 733-42.

Krishna MMG, Englander SW., The N-terminal to C-terminal motif in protein folding and function, Proc Natl Acad Sci USA, 2005; 102: 1053-8.

Chung JJ, Shikano S, Hanyu Y, Li M., Functional diversity of protein C-termini: more than zipcoding? Trends Cell Biol, 2002; 12: 146-50.

Fitzpatrick P, Shattil SJ, Ablooglu AJ., Carboxy-terminal-COOH of integrin β1 is necessary for β1 association with the kindlin-2 adapter protein, J Biol Chem, 2014; 289: 11183-93.

Curtis FA, Reed P, Wilson LA, Bowers LY, Yeo RP, Sanderson JM, Walmsley AR, Sharples GJ., The C-terminus of the phage λ Orf recombinase is involved in DNA binding, J Mol Recognit, 2010; 24: 333-340.

Wang HG, Rikitake Y, Carter MC, Yaciuk P, Abraham SE, Zerler B, Moran E., Identification of specific adenovirus E1A N-terminal residues critical to the binding of cellular proteins and to the control of cell growth, J Virol, 1993; 67: 476-88.

Chen J, Skehel JJ, Wiley DC., N-and C-terminal residues combine in the fusion-pH influenza hemagglutinin HA2 subunit to form an N cap that terminates the triple-stranded coiled coil, Proc Natl Acad Sci USA, 1999; 96: 8967-72.

Rost B, Sander C., Conservation and prediction of solvent accessibility in protein families. Proteins, 1994; 20: 216-26.

Friedman R, Nachliel E, Gutman M., Molecular dynamics of a protein surface: ion-residues interactions, Biophys J, 2005; 89: 768-81.

Pal D, Chakrabarti P., Terminal residues in protein chains: residue preference, conformation, and interaction, Biopolymers, 2000; 53: 467-475.

Rajasri B, Pal D, Chakrabarti P., Secondary structures at polypeptide-chain termini and their features, Acta Crystallogr D Biol Crystallogr, 2002; 58: 1793-802.

Austin RS, Provart NJ, Cutler SR., (2007) C-terminal motif prediction in eukaryotic proteomes using comparative genomics and statistical over-representation across protein families, BMC genomics, 2007; 8: 191.

Javier S, Serrano L, Fersht AR., Histidine residues at the N-and C-termini of. alpha.-helixes: perturbed pKas and protein stability, Biochemistry, 1992; 31: 2253-58.

Takahashi E, Kobayashi H, Yamanaka H, Nakanishi M, Tateishi A, Abet T, Arimoto S, Negishi T, Okamoto K., Analysis of carboxy terminal domain of metalloprotease of elastolytic Aeromonas hydrophila, Biol Pharma Bull, 2013; 36: 1174-82.

Nelson TK, Sorgen PL, Burt JM., Carboxy terminus and pore-forming domain properties specific to Cx37 are necessary for Cx37-mediated suppression of insulinoma cell proliferation, Am J Physiol-Cell, 2013; 305: C1246-C56.

Kozma D, Simon I, Tusnády GE., PDBTM: Protein Data Bank of transmembrane proteins after 8 years, Nucleic Acids Res, 2013; 41: D524-D9.

Rose PW, Bi C, Bluhm WF, Christie CH, Dimitropoulos D, et al., The RCSB Protein Data Bank: new resources for research and education, Nucleic Acids Res, 2013; 41: D475-D82.

Singh H, Chauhan JS, Gromiha MM, Consortium OSDD, Raghava GPS., ccPDB: compilation and creation of data sets from Protein Data Bank, Nucleic Acids Res, 2012; 40: D486-9.

Parthiban V, Gromiha MM, Schomburg D., CUPSAT: Prediction of protein stability upon point mutations, Nucleic Acids Res, 2006; 34, W239-42.

Cock H, Struyve M, Kleerebezem M, Krift TV, Tommassen J., Role of the Carboxy-terminal Phenylalanine in the Biogenesis of Outer Membrane Protein PhoE of Escherichia coli K-12, J Mol Biol, 1997; 269: 473-478.

Saravanan KM, Selvaraj S., Search for identical octapeptides in unrelated proteins: Structural plasticity revisited, Biopolymers, 2012; 98: 11-26.

Saravanan KM, Krishnaswamy S., Analysis of dihedral angle preferences for alanine and glycine residues in alpha and beta transmembrane regions, J Biomol Struct Dyn, 2014; DOI:10.1080/07391102.2014.895678.

Javadpour MM, Eilers M, Groesbeek M, Smith SO., Helix packing in polytopic membrane proteins: role of glycine in transmembrane helix association, Biophysical J, 1999; 77: 1609-18.

Ho BK, Brasseur R., The Ramachandran plots of glycine and pre-proline, BMC Struct Biol, 2005; 5: 14.

Adamczak R, Porollo A, Meller J., Combining prediction of secondary structure and solvent accessibility in proteins, Proteins, 2005; 59: 467-75.

Saravanan KM, Balasubramanian H, Nallusamy S, Samuel S., Sequence and structural analysis of two designed proteins with 88% identity adopting different folds, Protein Eng Des Sel, 2010; 23: 911-918.

Saravanan, KM, Selvaraj S., Performance of secondary structure prediction methods on proteins containing conformationally ambivalent sequence fragments, Biopolymers, 2012; 100:148-53.

Saravanan KM, Selvaraj S., Search and Analysis of Identical Reverse Octapeptides in Unrelated Proteins, Genomics, Proteomics Bioinformatics, 2013; 11: 114-21.

Gromiha MM., Influence of cation–π interactions in different folding types of membrane proteins, Biophy Chem, 2003; 103: 251-258.

Saravanan KM, Selvaraj S., Analysis and Visualization of Long-Range Contacts and Networks in Homologous Families of Proteins, Open Struct Biol J, 2009; 3: 104-125.