Conformational diversity analysis reveals three functional mechanisms in proteins
This paper was published recently in Plos Comp Bio and looks at the conformational diversity (flexibility) of protein structures by comparing solved structures of identical sequences.
The premise of the work is that different crystal structures of the same protein represent instances of the conformational space of the protein. These different instances are identical in amino acid sequence but often differ in other ways they could come from different crystal forms or the protein could have different co-factors bound or have undergone post translational modifications.
The data set used in the paper came from CoDNaS (conformational diversity of the native state) Database URL:http://ufq.unq.edu.ar/codnas.
Only structures solved using X-ray crystallography to a resolution better than 2.5A were used and only proteins for which at least 5 conformers were available (average of 15.53 conformers per protein). Just under 5000 different protein chains made up the set. In order to describe the protein chains the measure used was maximum conformational diversity (the maximum RMSD between any of the conformers of a given protein chain).
The authors describe a relationship between this maximum conformational diversity and the presence absence of intrinsically disordered regions (IDRs). An IDR was defined as a segment of at least 5 contiguous residues with missing electron density (the first and last 20 residues of the chain were not included).
The proteins were divided into three groups.
- IDRs in at least one conformer
- IDR in the maximum RMSD pair of conformational diversity
- IDRs in at least one conformer
- No IDR in the maximum RMSD pair of conformational diversity
Rigid proteins have in general lower conformational diversity than partially disordered than Malleable. The authors describe how these differences are not due to crystallographic conditions, protein length, number of crystal contacts or number of conformers.
The authors then go on to compare other properties based on these three types of protein chains including amino acid composition, loop RMSD and cavities and tunnels.
They summarise their findings with the figure below.
This paper Pechmann et al discusses the relationship between codons and co-translational regulation of protein folding. Every amino acid apart from Methionine and Tryptophan has multiple codons and it is well established that codons are translated at varying speeds and thus influence local translational kinetics.
This codon multiplicity and speed variation may be important for protein folding as several experiments have shown that synonymous substitutions (changing the codon but not the amino acid) alter folding and or function.
codon translation efficeincy depends on tRNA supply and demand
The new idea presented in this paper is a translational efficiency scale. This is an attempt to calculate the efficiency with which a codon will be translated by considering both the supply of tRNA and the demand for that tRNA. They calculate their new measure nTE for all of the coding sequences in 10 closely related yeast species.
The distribution of the nTE values is unlike that of previous scales as the majority of codons occur in a middle plateau region. The authors suggest that this is due to cost effective proteome maintenance, i.e. for most tRNA supply and demand are closely matched.
They go on to look for the previously observed “ramp” a slow region at the start of coding sequences. They identify a ramp region which is approximately 10 codons long (this is significantly shorter than that seen in other analyses which found a 35-50 codon ramp). This shorter region relates to two other observations, firstly the distance between the peptidyl transferase centre and the constriction site in the ribosome is approximately 10 amino acids long and secondly that experimentally ribosomes are found to pause near the very start of coding sequences.
The codons are now divided into two categories based on their nTE score, optimal codons those with high nTE values that should be translated rapidly and accurately and non-optimal codons. The authors found that codon optimality was conserved between orthologs in their set at rates far higher than those expected by chance (for both optimal and non-optimal codons). When considering those proteins with structural information available, they were also able to observe conservation of positioning of codon types with respect to secondary structures. This evolutionary conservation suggests an evolved function for codon optimality in regulating the rhythm of elongation in order to facilitate co-translational protein folding.
Evolutionary conservation of codon optimality reveals hidden signatures of cotranslational folding Nat Struct Mol Biol. 2013 Feb;20(2):237-43 Pechmann S, Frydman J.