The Combined Effects of Amino Acid Substitutions and Indels on the Evolution of Structure within Protein Families

BACKGROUND: In the process of protein evolution, sequence variations within protein families can cause changes in protein structures and functions. However, structures tend to be more conserved than sequences and functions. This leads to an intriguing question: what is the evolutionary mechanism by which sequence variations produce structural changes? To investigate this question, we focused on the most common types of sequence variations: amino acid substitutions and insertions/deletions (indels). Here their combined effects on protein structure evolution within protein families are studied. RESULTS: Sequence-structure correlation analysis on 75 homologous structure families (from SCOP) that contain 20 or more non-redundant structures shows that in most of these families there is, statistically, a bilinear correlation between the amount of substitutions and indels versus the degree of structure variations. Bilinear regression of percent sequence non-identity (PNI) and standardized number of gaps (SNG) versus RMSD was performed. The coefficients from the regression analysis could be used to estimate the structure changes caused by each unit of substitution (structural substitution sensitivity, SSS) and by each unit of indel (structural indel sensitivity, SIDS). An analysis on 52 families with high bilinear fitting multiple correlation coefficients and statistically significant regression coefficients showed that SSS is mainly constrained by disulfide bonds, which almost have no effects on SIDS. CONCLUSIONS: Structural changes in homologous protein families could be rationally explained by a bilinear model combining amino acid substitutions and indels. These results may further improve our understanding of the evolutionary mechanisms of protein structures

A Membrane Fusion Protein αSNAP Is a Novel Regulator of Epithelial Apical Junctions

Tight junctions (TJs) and adherens junctions (AJs) are key determinants of the structure and permeability of epithelial barriers. Although exocytic delivery to the cell surface is crucial for junctional assembly, little is known about the mechanisms controlling TJ and AJ exocytosis. This study was aimed at investigating whether a key mediator of exocytosis, soluble N-ethylmaleimide sensitive factor (NSF) attachment protein alpha (αSNAP), regulates epithelial junctions. αSNAP was enriched at apical junctions in SK-CO15 and T84 colonic epithelial cells and in normal human intestinal mucosa. siRNA-mediated knockdown of αSNAP inhibited AJ/TJ assembly and establishment of the paracellular barrier in SK-CO15 cells, which was accompanied by a significant down-regulation of p120-catenin and E-cadherin expression. A selective depletion of p120 catenin effectively disrupted AJ and TJ structure and compromised the epithelial barrier. However, overexpression of p120 catenin did not rescue the defects of junctional structure and permeability caused by αSNAP knockdown thereby suggesting the involvement of additional mechanisms. Such mechanisms did not depend on NSF functions or induction of cell death, but were associated with disruption of the Golgi complex and down-regulation of a Golgi-associated guanidine nucleotide exchange factor, GBF1. These findings suggest novel roles for αSNAP in promoting the formation of epithelial AJs and TJs by controlling Golgi-dependent expression and trafficking of junctional proteins

A horizontal alignment tool for numerical trend discovery in sequence data: application to protein hydropathy.

PMC3794901An algorithm is presented that returns the optimal pairwise gapped alignment of two sets of signed numerical sequence values. One distinguishing feature of this algorithm is a flexible comparison engine (based on both relative shape and absolute similarity measures) that does not rely on explicit gap penalties. Additionally, an empirical probability model is developed to estimate the significance of the returned alignment with respect to randomized data. The algorithm's utility for biological hypothesis formulation is demonstrated with test cases including database search and pairwise alignment of protein hydropathy. However, the algorithm and probability model could possibly be extended to accommodate other diverse types of protein or nucleic acid data, including positional thermodynamic stability and mRNA translation efficiency. The algorithm requires only numerical values as input and will readily compare data other than protein hydropathy. The tool is therefore expected to complement, rather than replace, existing sequence and structure based tools and may inform medical discovery, as exemplified by proposed similarity between a chlamydial ORFan protein and bacterial colicin pore-forming domain. The source code, documentation, and a basic web-server application are available.JH Libraries Open Access Fun

A modular perspective of protein structures: application to fragment based loop modeling

Proteins can be decomposed into supersecondary structure modules. We used a generic definition of supersecondary structure elements, so-called Smotifs, which are composed of two flanking regular secondary structures connected by a loop, to explore the evolution and current variety of structure building blocks. Here, we discuss recent observations about the saturation of Smotif geometries in protein structures and how it opens new avenues in protein structure modeling and design. As a first application of these observations we describe our loop conformation modeling algorithm, ArchPred that takes advantage of Smotifs classification. In this application, instead of focusing on specific loop properties the method narrows down possible template conformations in other, often not homologous structures, by identifying the most likely supersecondary structure environment that cradles the loop. Beyond identifying the correct starting supersecondary structure geometry, it takes into account information of fit of anchor residues, sterical clashes, match of predicted and observed dihedral angle preferences, and local sequence signal