Polyproline, conformation

A). This conformation is very similar to that of collagen (Dickerson and Geis, 1969 Schellmann and Schellmann, 1964). Of these regular structures, only segments of polyproline conformation can exist in globular proteins. 

Figure 13.30 Ribbon diagram of the structure of Src tyrosine kinase. The structure is divided in three units starting from the N-terminus an SH3 domain (green), an SH2 domain (blue), and a tyrosine kinase (orange) that is divided into two domains and has the same fold as the cyclin dependent kinase described in Chapter 6 (see Figure 6.16a). The linker region (red) between SH2 and the kinase is bound to SH3 in a polyproline helical conformation. A tyrosine residue in the carboxy tail of the kinase is phosphorylated and bound to SH2 in its phosphotyrosine-binding site. A disordered part of the activation segment in the kinase is dashed. (Adapted from W. Xu et al.. Nature 385 595-602, 1997.)...

Src tyrosine kinase contains both an SH2 and an SH3 domain linked to a tyrosine kinase unit with a structure similar to other protein kinases. The phosphorylated form of the kinase is inactivated by binding of a phosphoty-rosine in the C-terminal tail to its own SH2 domain. In addition the linker region between the SH2 domain and the kinase is bound in a polyproline II conformation to the SH3 domain. These interactions lock regions of the active site into a nonproductive conformation. Dephosphorylation or mutation of the C-terminal tyrosine abolishes this autoinactivation. 

Jardetzky, T.5., Wiley, D.C. Crystallographic analysis of endogenous peptides associated with HLA-DRl suggests a common, polyproline Il-like conformation for hound peptides. Proc. Natl. Acad. Sci. USA 93 734-728, 1996. 

Molecular insight into the protein conformation states of Src kinase has been revealed in a series of x-ray crystal structures of the Src SH3-SH2-kinase domain that depict Src in its inactive conformation [7]. This form maintains a closed structure, in which the tyrosine-phosphorylated (Tyr527) C-terminal tail is bound to the SH2 domain (Fig. 2). The x-ray data also reveal binding of the SH3 domain to the SH2-kinase linker [adopts a polyproline type II (PP II) helical conformation], providing additional intramolecular interactions to stabilize the inactive conformation. Collectively, these interactions cause structural changes within the catalytic domain of the protein to compromise access of substrates to the catalytic site and its associated activity. Significantly, these x-ray structures provided the first direct evidence that the SH2 domain plays a key role in the self-regulation of Src. 

IS POLYPROLINE II A MAJOR BACKBONE CONFORMATION IN UNFOLDED PROTEINS ... 

T. P. Creamer (unpublished results). A plot of estimated (ASA) against %PPII content is given in Figure 5. At first glance, it would appear that there is little correlation between the two properties. However, three residues—proline, glycine, and glutamine—can be considered outliers, each for a specific reason. Proline has a high %PPII content in the polyproline-based host peptide used by Kelly et al. (2001) as a result of its unique properties as an imine. As discussed above, a proline that is followed in sequence by a second proline is restricted to the PPII conformation by steric interactions. 

What is the origin of the energy difference between the polyproline II and /J-strand backbone conformations Brant and Flory (1965b) emphasize the important roles of steric clash, dipole-dipole interactions (see also Avbelj and Moult, 1995), and the torsional potentials governing rotation about the backbone ,t/i angles (see also Flory, 1969). An ab initio quantum mechanics study (Han et al., 1998 see also references therein to earlier work) finds that solvation by water is important. The authors examine the predicted stabilities of eight conformers of... 

Experimental and theoretical approaches are now converging on the polyproline II backbone conformation as the most stable structure for short alanine peptides in water. It becomes of urgent importance to determine the energy differences between polyproline II and other possible backbone conformations, as well as to determine how amino acid composition and sequence affect backbone conformation. 

Mykhailiuk PK, Afonin S, Palamarchuk GV, Shishkin OV, Ulrich AS, Komarov IV (2008) Synthesis of trifluoromethyl-substituted proline analogues as F-19 NMR labels for peptides in the polyproline II conformation. Angew Chem Int Edit 47 5765-5767... 

A few other helical conformations occur occasionally in globular protein structures. The polyproline helix, of the same sort as one strand out of a collagen structure, has been found in pancreatic trypsin inhibitor (Huber et al., 1971) and in cytochrome c551 (Almassy and Dickerson, 1978). An extended e helix has been described as occurring in chymotrypsin (Srinivasan et al., 1976). In view of the usual variability and irregularity seen in local protein conformation it is unclear that either of these last two helix types is reliably distinguishable from simply an isolated extended strand however, the presence of prolines can justify the designation of polyproline helix. 

The next three sections (Sections 7.7.1, 7.7.2, and 7.7.3) cover fluorescence spectroscopy, I15-18 infrared, and circular dichroism, three powerful approaches to characterize the structure and conformational considerations of synthetic peptides. Section 7.7.1 deals with the use of fluorophores and broad aspects of fluorescence spectroscopy to characterize conformational aspects of peptide structure. In a similar manner, Section 7.7.2 covers a broad aspect of the uses of infrared (IR) techniques to study peptide conformations 19-22 Many IR techniques are discussed, as are approaches for the study of specific peptidic structures including amyloid, p-turn, and membrane peptides. Finally, there is a section on circular dichroism (Section 7.7.3) that covers the major issues of concern for peptide synthetic chemists such as the assignments of a-helix, 310-helix, -sheets and P-turns, and polyproline helices 23-25 There is also a brief description of cyclic peptides. 

Minimum energy conformations of proline oligomers and polyd-proline) are calculated. The left-hand helix of Vans-polyproline 11 becomes stable at the tetramer, whereas the right-hand helix of the c/s-polyproline 1 is not established until at least the pentamer. The potential minima include values of v (v = 163° wans, xy = 56° cis) which yiaid forms of the polymer that are virtually identical with polyproline 1 and 11 in the solid state. 

---