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.

Phosphorylation-dependent Changes in Nucleotide Binding, Conformation, and Dynamics of the First Nucleotide Binding Domain (NBD1) of the Sulfonylurea Receptor 2B (SUR2B)

“…Residue Thr-632 corresponds to a canonical PKA phosphorylation site that is conserved among species, and residue Ser-636 is a variable noncanonical PKA phosphorylation site. Residue Ser-636 in rat and murine SUR2B corresponds to a Pro residue (Pro-639) in human SUR2B, which would promote alternative conformations of the N-terminal tail (77,78). Furthermore, Pro-639 is part of exon 14 (residues Gln-638 -Lys-673) that is missing in a naturally occurring splice isoform, known as human SUR2C (79), which further illustrates the regulatory nature of the N-terminal tail.…”

Structural Analysis of an Avr4 Effector Ortholog Offers Insight into Chitin Binding and Recognition by the Cf-4 Receptor

“…This residue is also conserved in Pf-Avr4 (Pro-83) and is located in a relatively neutral loop region that is N-terminal to the ChtBD domain. However, as prolines are structurally important residues with a pivotal role in directing protein folding (MacArthur and Thornton, 1991;Deber et al, 2010), it is plausible that mutating this residue would alter the structure of the b-hairpin loop that encompasses the ChtBD domain, thereby rendering the protein sensitive to proteolytic degradation (Mesarich et al, 2016). Indeed, an alanine substitution of Pro-83 in Pf-Avr4 resulted in a partially unstable protein that triggers a Cf-4-mediated HR, as seen by treatment of the protein with subtilisin and infiltrations in cv Purdue 135 (+Cf-4) (Supplemental Figure 9).…”

The Ambivalent Role of Proline Residues in an Intrinsically Disordered Protein: From Disorder Promoters to Compaction Facilitators

“…These steric restraints reduce the energy difference between cis/trans conformers involving peptide bonds between proline residues and the amino acids preceding them (Xaa-Pro peptide bonds). While for non-cyclic amino acids the occurrence of the cis conformation is less than a 0.5%, the cyclic nature of prolines slightly disfavors the trans conformation, leading to increased cis populations, typically ranging from 5 to 10% [5,6].…”