Proline Residues in Proteins

Abstract

As the only commonly occurring imino acid in proteins, proline has been found to play unique structural and dynamic roles in guiding protein folding, fibre formation and protein–protein interactions. The cyclic pyrrolidine side‐chain fixes the backbone dihedral ϕ angle and renders proline unable to act as a hydrogen bond donor. These properties are reflected in its preference for protein secondary structure elements such as turns and polyproline II helices, and its generally destabilizing effect on α helix and β‐strand conformation. The ability of proline to undergo cis‐trans isomerization is important in protein folding and forms the basis of molecular switches that help to control cellular growth and regulation. Proline and its posttranslationally modified analogue, hydroxyproline, are additionally the major components of collagens, proteins that are the major fibrous proteins in animals and account for approximately 30% of total human body protein.

Key Concepts:

  • The structural and dynamic properties imparted to proteins by the amino acid proline arise from the unique cyclic structure of its side‐chain.

  • Interconversion of proline from cis to trans conformation, which can be facilitated by peptidylprolyl isomerases, is a rate‐limiting step in protein folding and can act as a molecular switch in the regulation of cellular growth and signalling.

  • Proline residues facilitate the formation of protein secondary structure elements such as turns and the polyproline II helix, but typically disfavour α helix and β‐strand conformations.

  • Proline and its posttranslationally modified analogue hydroxyproline are key components of the structural protein collagen.

  • Regions of water‐soluble proteins rich in proline residues are often sites of protein–protein interaction.

Keywords: proline; hydroxyproline; collagen; polyproline II helix; protein–protein interactions; peptidylprolyl isomerase

Figure 1.

Chemical structures of (a) a proline (Pro) residue and (b) a hydroxyproline (Hyp) residue.

Figure 2.

The nature of Pro interactions and its properties in an α helix. The Pro residue unit is highlighted in the shaded area. The nitrogen (N), carbonyl oxygen (O) and pyrrolidine ring carbons (Greek letters) are indicated, as are the standard protein backbone angles (ϕ, ψ). The full diagram depicts the Pro residue as part of a segment of a helix, with atoms of the other amino acid residues shown in black (carbon), dark grey (oxygen) and light grey (nitrogen). The specific properties and characteristics conferred by a Pro residue on the overall structure are described in the text within the diagram.

Figure 3.

Representation of the different levels of collagen structure. (a) Chemical structure of glycyl‐prolyl‐hydroxyprolyl (Gly‐Pro‐Hyp), the most common tripeptide in the repeating Gly‐X‐Y triad sequence. (b) The molecular conformation of the collagen triple‐helix. (c) Diagram of the axial arrangement of collagen molecules in typical collagen fibrils. Adjacent molecules are staggered axially by 67 nm, generating an axial repeat that can be seen in the electron micrograph of the collagen fibril shown. Each 67 nm repeat contains a dark band (gap region) and a light band (overlap region).

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References

Adzhubei AA and Sternberg MJ (1993) Left‐handed polyproline II helices commonly occur in globular proteins. Journal of Molecular Biology 229: 472–493.

Ball LJ, Jarchau T, Oschkinat H and Walter U (2002) EVH1 domains: structure, function and interactions. FEBS Letters 513: 45–52.

Barlow DJ and Thornton JM (1988) Helix geometry in proteins. Journal of Molecular Biology 201: 601–619.

Baum J and Brodsky B (1997) Real‐time NMR investigations of triple‐helix folding and collagen folding diseases. Folding & Design 2: R53–60.

Bella J, Eaton M, Brodsky B and Berman HM (1994) Crystal and molecular structure of a collagen‐like peptide at 1.9 Å resolution. Science 266: 75–81.

Bhattacharyya A, Thakur AK, Chellgren VM et al. (2006) Oligoproline effects on polyglutamine conformation and aggregation. Journal of Molecular Biology 355: 524–535.

Brandts JF, Halvorson HR and Brennan M (1975) Consideration of the possibility that the slow step in protein denaturation reactions is due to cis‐trans isomerism of proline residues. Biochemistry 14: 4953–4963.

Brazin KN, Mallis RJ, Fulton DB and Andreotti AH (2002) Regulation of the tyrosine kinase Itk by the peptidyl‐prolyl isomerase cyclophilin A. Proceedings of the National Academy of Sciences of the USA 99: 1899–1904.

Cabral WA, Chang W, Barnes AM et al. (2007) Prolyl 3‐hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nature Genetics 39: 359–365.

Carlson DM (1993) Salivary proline‐rich proteins: biochemistry, molecular biology, and regulation of expression. Critical Reviews in Oral Biology and Medicine 4: 495–502.

Chou PY and Fasman GD (1974) Conformational parameters for amino acids in helical, beta‐sheet, and random coil regions calculated from proteins. Biochemistry 13: 211–222.

Chou PY and Fasman GD (1978) Empirical predictions of protein conformation. Annual Review of Biochemistry 47: 251–276.

Cowan PM and McGavin S (1955) Structure of poly L‐proline. Nature 176: 501–503.

Dang H, England PM, Farivar SS, Dougherty DA and Lester HA (2000) Probing the role of a conserved M1 proline residue in 5‐hydroxytryptamine(3) receptor gating. Molecular Pharmacology 57: 1114–1122.

Darnell G, Orgel JP, Pahl R and Meredith SC (2007) Flanking polyproline sequences inhibit beta‐sheet structure in polyglutamine segments by inducing PPII‐like helix structure. Journal of Molecular Biology 374: 688–704.

Deber CM, Brandl CJ, Deber RB, Hsu LC and Young XK (1986) Amino acid composition of the membrane and aqueous domains of integral membrane proteins. Archives of Biochemistry and Biophysics 251: 68–76.

Deber CM and Therien AG (2002) Putting the beta‐breaks on membrane protein misfolding. Nature Structural Biology 9: 318–319.

Engel J, Chen HT, Prockop DJ and Klump H (1977) The triple helix in equilibrium with coil conversion of collagen‐like polytripeptides in aqueous and nonaqueous solvents. Comparison of the thermodynamic parameters and the binding of water to (L‐Pro‐L‐Pro‐Gly)n and (L‐Pro‐L‐Hyp‐Gly)n. Biopolymers 16: 601–622.

Fischer G, Wittmann‐Liebold B, Lang K, Kiefhaber T and Schmid FX (1989) Cyclophilin and peptidyl‐prolyl cis‐trans isomerase are probably identical proteins. Nature 337: 476–478.

Fu D, Libson A, Miercke LJ et al. (2000) Structure of a glycerol‐conducting channel and the basis for its selectivity. Science 290: 481–486.

Henderson R, Baldwin JM, Ceska TA et al. (1990) Model for the structure of bacteriorhodopsin based on high‐resolution electron cryo‐microscopy. Journal of Molecular Biology 213: 899–929.

Hutchinson EG and Thornton JM (1994) A revised set of potentials for beta‐turn formation in proteins. Protein Science 3: 2207–2216.

Ilsley JL, Sudol M and Winder SJ (2002) The WW domain: linking cell signalling to the membrane cytoskeleton. Cell Signal 14: 183–189.

Jabs A, Weiss MS and Hilgenfeld R (1999) Non‐proline cis peptide bonds in proteins. Journal of Molecular Biology 286: 291–304.

Kaneko T, Li L and Li SS (2008) The SH3 domain – a family of versatile peptide‐ and protein‐recognition module. Frontier of Bioscience 13: 4938–4952.

Kay BK, Williamson MP and Sudol M (2000) The importance of being proline: the interaction of proline‐rich motifs in signaling proteins with their cognate domains. FASEB Journal 14: 231–241.

Kentsis A, Mezei M, Gindin T and Osman R (2004) Unfolded state of polyalanine is a segmented polyproline II helix. Proteins 55: 493–501.

Kentsis A, Mezei M and Osman R (2005) Origin of the sequence‐dependent polyproline II structure in unfolded peptides. Proteins 61: 769–776.

Kivirikko KI and Pihlajaniemi T (1998) Collagen hydroxylases and the protein disulfide isomerase subunit of prolyl 4‐hydroxylases. Advances in Enzymology and Related Areas of Molecular Biology 72: 325–398.

Kofler MM and Freund C (2006) The GYF domain. FEBS Journal 273: 245–256.

Lise S and Jones DT (2005) Sequence patterns associated with disordered regions in proteins. Proteins 58: 144–150.

Lu KP, Finn G, Lee TH and Nicholson LK (2007) Prolyl cis‐trans isomerization as a molecular timer. Nature Chemical Biology 3: 619–629.

Luecke H, Schobert B, Richter HT, Cartailler JP and Lanyi JK (1999) Structure of bacteriorhodopsin at 1.55 Å resolution. Journal of Molecular Biology 291: 899–911.

Lummis SC, Beene DL, Lee LW et al. (2005) Cis‐trans isomerization at a proline opens the pore of a neurotransmitter‐gated ion channel. Nature 438: 248–252.

Mallis RJ, Brazin KN, Fulton DB and Andreotti AH (2002) Structural characterization of a proline‐driven conformational switch within the Itk SH2 domain. Nature Structural Biology 9: 900–905.

Mezei M, Fleming PJ, Srinivasan R and Rose GD (2004) Polyproline II helix is the preferred conformation for unfolded polyalanine in water. Proteins 55: 502–507.

Mohs A, Silva T, Yoshida T et al. (2007) Mechanism of stabilization of a bacterial collagen triple helix in the absence of hydroxyproline. Journal of Biological Chemistry 282: 29757–29765.

Moriarty DF and Raleigh DP (1999) Effects of sequential proline substitutions on amyloid formation by human amylin 20–29. Biochemistry 38: 1811–1818.

Myllyharju J (2008) Prolyl 4‐hydroxylases, key enzymes in the synthesis of collagens and regulation of the response to hypoxia, and their roles as treatment targets. Annals of Medicine 40: 402–417.

Nilsson I, Saaf A, Whitley P et al. (1998) Proline‐induced disruption of a transmembrane alpha‐helix in its natural environment. Journal of Molecular Biology 284: 1165–1175.

Nilsson I and von Heijne G (1998) Breaking the camel's back: proline‐induced turns in a model transmembrane helix. Journal of Molecular Biology 284: 1185–1189.

O'Neil KT and DeGrado WF (1990) A thermodynamic scale for the helix‐forming tendencies of the commonly occurring amino acids. Science 250: 646–651.

Privalov PL (1982) Stability of proteins. Proteins which do not present a single cooperative system. Advances in Protein Chemistry 35: 1–104.

Ramachandran GN (1988) Stereochemistry of collagen. International Journal of Peptide and Protein Research 31: 1–16.

Rath A, Davidson AR and Deber CM (2005) The structure of “unstructured” regions in peptides and proteins: role of the polyproline II helix in protein folding and recognition. Biopolymers 80: 179–185.

Ricard‐Blum S and Ruggiero F (2005) The collagen superfamily: from the extracellular matrix to the cell membrane. Pathologie et Biologie (Paris) 53: 430–442.

Rich A and Crick FH (1961) The molecular structure of collagen. Journal of Molecular Biology 3: 483–506.

Sarkar P, Reichman C, Saleh T, Birge RB and Kalodimos CG (2007) Proline cis‐trans isomerization controls autoinhibition of a signaling protein. Molecular Cell 25: 413–426.

Shi Z, Woody RW and Kallenbach NR (2002) Is polyproline II a major backbone conformation in unfolded proteins? Advances in Protein Chemistry 62: 163–240.

Shoulders MD and Raines RT (2009) Collagen structure and stability. Annual Review of Biochemistry 78: 929–958.

Sreerama N and Woody RW (1994) Poly(pro)II helices in globular proteins: identification and circular dichroic analysis. Biochemistry 33: 10022–10025.

Sreerama N and Woody RW (1999) Molecular dynamics simulations of polypeptide conformations in water: a comparison of alpha, beta, and poly(pro)II conformations. Proteins 36: 400–406.

Stapley BJ and Creamer TP (1999) A survey of left‐handed polyproline II helices. Protein Science 8: 587–595.

Stewart DE, Sarkar A and Wampler JE (1990) Occurrence and role of cis peptide bonds in protein structures. Journal of Molecular Biology 214: 253–260.

Suchyna TM, Xu LX, Gao F, Fourtner CR and Nicholson BJ (1993) Identification of a proline residue as a transduction element involved in voltage gating of gap junctions. Nature 365: 847–849.

Wigley WC, Corboy MJ, Cutler TD et al. (2002) A protein sequence that can encode native structure by disfavoring alternate conformations. Nature Structural Biology 9: 381–388.

Williams KA and Deber CM (1991) Proline residues in transmembrane helices: structural or dynamic role? Biochemistry 30: 8919–8923.

Further Reading

Deber CM, Madison V and Blout ER (1976) Why cyclic peptides: complementary approaches to conformations. Accounts of Chemical Research 9: 106–112.

Freund C, Schmalz H G, Sticht J and Kuhne R (2008) Proline‐rich sequence recognition domains (PRD): ligands, function and inhibition. Handbook of Experimental Pharmacology 186: 407–429.

Kielty CM, Hopkinson I and Grant MI (1993) The collagen family: structure, assembly, and organization in the extracellular matrix. In: Royce PM and Steinmann B (ed.) Connective Tissue and Its Hereditable Disorders: Molecular, Genetic, and Medical Aspects, pp. 103–148. New York: Wiley‐Liss.

Krane SM (2008) The importance of proline residues in the structure, stability and susceptibility to proteolytic degradation of collagens. Amino Acids 35: 703–710.

Richardson JS and Richardson DC (1989) Principles and patterns of protein conformation. In: Fasman GD (ed.) Prediction of Protein Structure and the Principles of Protein Conformation, pp. 1–99. New York: Plenum Press.

Sansom MS and Weinstein H (2000) Hinges, swivels and switches: the role of prolines in signalling via transmembrane alpha‐helices. Trends in Pharmacological Science 21: 445–451.

Smith JA and Pease LG (1980) Reverse turns in peptides and proteins. CRC Critical Reviews in Biochemistry 8: 315–399.

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Deber, Charles M, Brodsky, Barbara, and Rath, Arianna(Apr 2010) Proline Residues in Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003014.pub2]