Local Interactions in Protein Folding: Lessons from the α-Helix

Aurora, Rajeev; Creamer, T.; Srinivasan, R.; Rose, George D.

doi:10.1074/jbc.272.3.1413

Cited by 147 publications

(118 citation statements)

References 81 publications

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“…One is left to conclude that an isolated alanine has a high propensity to adopt this conformation. The propensity for multiple alanines to favor the R-helical conformation is well-known, due in large part to intramolecular hydrogen bond formation and good van der Waals interactions (39). Such hydrogen bonds, and van der Waals interactions, are precluded in the peptides employed here.…”

Section: Resultsmentioning

confidence: 99%

Host−Guest Study of Left-Handed Polyproline II Helix Formation

et al. 2001

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The importance of the left-handed polyproline II (PPII) helical conformation has recently become apparent. This conformation generally is involved in two important functions: protein-protein interactions and structural integrity. PPII helices play vital roles in a variety of processes including signal transduction, transcription, and cell motility. Proline-rich regions of sequence are often assumed to adopt this structure. Remarkably, little is known about the physical determinants of this secondary structure type. In this study, we have explored the formation of PPII helices by a short poly(proline) peptide. In addition, the results from experiments used to determine the propensities for apolar residues, plus glycine, asparagine, and glutamine, to adopt this structure in a poly(proline)-based host peptide are reported here. Proline possesses the highest intrinsic propensity, with glutamine, alanine, and glycine having surprisingly high propensities.-Branched residues possess the lowest propensities of the residues examined. It is postulated that propensities possessed by apolar residues are due in part to peptide-solvent interactions, and that the remarkably high propensity possessed by glutamine may be due to a side chain to backbone hydrogen bond. These data are the first step toward a molecular understanding of the formation of this important, and yet little studied, secondary structure.In recent years, the left-handed polyproline II (PPII) 1 helical conformation has been elevated from the status of a relatively rare and seemingly uninteresting secondary structure to one that is surprisingly common and of the utmost importance. This structure plays a central role in numerous vital processes including signal transduction, transcription, cell motility, and the immune response. Proline-rich ligands of the cytoskeletal protein profilin (1), as well as those of the SH3, WW, and EVH1 protein interaction domains, are bound in this conformation (2). The peptide ligands of class II MHC molecules are also bound in the PPII conformation (3). PPII helices are major features of collagens (4) and plant cell wall proteins (5). The PPII helix is believed to be the dominant conformation for many proline-rich regions of sequence (PRRs) (6). Sequences not rich in proline also adopt this structure. For example, poly(lysine), poly(glutamate), and poly(aspartate) peptides form PPII helices (7). Around 2% of all residues in known protein structures are found in PPII helices at least four residues long (8, 9). As many as 10% of all residues are found in the PPII conformation, although not necessarily as part of PPII helices (10). PPII helices have also been hypothesized to be a major component of protein denatured states (11-14), giving them a role in a most fundamental process. Recently, Blanch et al. (15) have suggested that the PPII helix might be the precursor conformation in amyloid formation. Given the preceding, it is truly remarkable how little is known about the physical determinants of the PPII helical conformat...

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Section: Resultsmentioning

confidence: 99%

Host−Guest Study of Left-Handed Polyproline II Helix Formation

et al. 2001

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“…Here, we mention some examples of proposed mechanisms. On the basis of entropic considerations, Rose et al suggest that helix and strand formation will be guiding events in protein folding (Aurora et al 1997;Baldwin and Rose 1999a, b;Dadlez 1999). Folding prediction by the fragment assembly mechanism, which is based mainly on early formed LIs, was successfully used by many groups (Levitt 1992;Bowie and Eisenberg 1994;Simons et al 1997;Lee et al 1999;Chikenji et al 2006;Haspel et al 2003a, b).…”

Section: O'neill Et Al (O'neill and Robert Matthews 2000)mentioning

confidence: 99%

The loop hypothesis: contribution of early formed specific non-local interactions to the determination of protein folding pathways

et al. 2013

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The extremely fast and efficient folding transition (in seconds) of globular proteins led to the search for some unifying principles embedded in the physics of the folding polypeptides. Most of the proposed mechanisms highlight the role of local interactions that stabilize secondary structure elements or a folding nucleus as the starting point of the folding pathways, i.e., a "bottom-up" mechanism. Nonlocal interactions were assumed either to stabilize the nucleus or lead to the later steps of coalescence of the secondary structure elements. An alternative mechanism was proposed, an "up-down" mechanism in which it was assumed that folding starts with the formation of very few non-local interactions which form closed long loops at the initiation of folding. The possible biological advantage of this mechanism, the "loop hypothesis", is that the hydrophobic collapse is associated with ordered compactization which reduces the chance for degradation and misfolding. In the present review the experiments, simulations and theoretical consideration that either directly or indirectly support this mechanism are summarized. It is argued that experiments monitoring the time-dependent development of the formation of specifically targeted early-formed sub-domain structural elements, either long loops or secondary structure elements, are necessary. This can be achieved by the timeresolved FRET-based "double kinetics" method in combination with mutational studies. Yet, attempts to improve the time resolution of the folding initiation should be extended down to the sub-microsecond time regime in order to design experiments that would resolve the classes of proteins which first fold by local or non-local interactions.

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“…The involvement of such simple sequences in a wide variety of functional roles might therefore explain their relative abundance. Alanine is known to be the most energetically favorable residue in ␣-helices (31,32). One might therefore expect that sequences that are 50% or greater alanine in composition will have a tendency to be ␣-helical, although this will of course be modulated by the nature of the other residues in the sequence as well as by the tertiary structure of the proteins they are part of.…”

Section: Residue Length Dependencesmentioning

confidence: 99%

Abundance and Distributions of Eukaryote Protein Simple Sequences

Sim

Creamer

2002

Molecular & Cellular Proteomics

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Protein simple sequences are a subclass of low complexity regions of sequence that are highly enriched in one or a few residue types. Such sequences are common in transcription regulatory proteins, in structural proteins, in proteins involved in nucleic acid interactions, and in mediating protein-protein interactions. Simple sequences of 10 or more residues, containing >50% of a single residue type are surveyed in this work. Both eukaryote and prokaryote proteomes are investigated with emphasis on the eukaryotes. Very large numbers of such sequences are found in all organisms surveyed. It is found that eukaryotes possess far more simple sequences per protein than do the prokaryotes. Prokaryotes display a linear relationship between number of proteins containing simple sequences and proteome size, whereas it is not clear that such a relationship holds for eukaryotes. Strikingly, it is found that each eukaryote possesses its own unique distribution of simple sequences. Within those distributions it is found that simple sequences enriched in certain residue types are clearly favored, whereas others are just as clearly discriminated against. The preferences observed are not correlated with residue occurrence. An analysis of classes of proteins of known function suggests that simple sequence occurrence and distribution may be related to protein function. Based upon this analysis, the large number of simple sequences found above that would be expected from a simple statistical model, plus the known functional importance of numerous such sequences, it is postulated that eukaryotes have evolved to not only tolerate large numbers of simple sequences but also to require them.

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Local Interactions in Protein Folding: Lessons from the α-Helix

Cited by 147 publications

References 81 publications

Host−Guest Study of Left-Handed Polyproline II Helix Formation

Host−Guest Study of Left-Handed Polyproline II Helix Formation

The loop hypothesis: contribution of early formed specific non-local interactions to the determination of protein folding pathways

Abundance and Distributions of Eukaryote Protein Simple Sequences

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