scholarly journals Inferring amino acid interactions underlying protein function

2017 ◽  
Author(s):  
Victor H. Salinas ◽  
Rama Ranganathan
Keyword(s):  
Amino Acid ◽  
Protein Function ◽  
Structural Basis ◽  
Evolutionary Divergence ◽  
Amino Acid Residues ◽  
Homologous Proteins ◽  
Physical Constraints ◽  
Spatially Distributed ◽  
Statistical Coupling ◽  
Energetic Interactions

Protein function arises from a poorly defined pattern of cooperative energetic interactions between amino acid residues. Strategies for deducing this pattern have been proposed, but lack of benchmark data has limited experimental verification. Here, we extend deep-mutation technologies to enable measurement of many thousands of pairwise amino acid couplings in members of a protein family. The data show that despite great evolutionary divergence, homologous proteins conserve a sparse, spatially distributed network of cooperative interactions between amino acids that underlies function. This pattern is quantitatively captured in the coevolution of amino acid positions, especially as indicated by the statistical coupling analysis (SCA), providing experimental confirmation of the key tenets of this method. This work establishes a clear link between physical constraints on protein function and sequence analysis, enabling a general practical approach for understanding the structural basis for protein function.

scholarly journals Coevolution-based inference of amino acid interactions underlying protein function

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Victor H Salinas ◽  
Rama Ranganathan
Keyword(s):  
Amino Acid ◽  
Protein Function ◽  
Structural Basis ◽  
Amino Acid Residues ◽  
Physical Constraints ◽  
Cooperative Interactions ◽  
Evolutionarily Conserved ◽  
Statistical Coupling ◽  
Energetic Interactions ◽  
Statistical Coupling Analysis

Protein function arises from a poorly understood pattern of energetic interactions between amino acid residues. Sequence-based strategies for deducing this pattern have been proposed, but lack of benchmark data has limited experimental verification. Here, we extend deep-mutation technologies to enable measurement of many thousands of pairwise amino acid couplings in several homologs of a protein family – a deep coupling scan (DCS). The data show that cooperative interactions between residues are loaded in a sparse, evolutionarily conserved, spatially contiguous network of amino acids. The pattern of amino acid coupling is quantitatively captured in the coevolution of amino acid positions, especially as indicated by the statistical coupling analysis (SCA), providing experimental confirmation of the key tenets of this method. This work exposes the collective nature of physical constraints on protein function and clarifies its link with sequence analysis, enabling a general practical approach for understanding the structural basis for protein function.

scholarly journals Evolution-Based Functional Decomposition of Proteins

2015 ◽  
Author(s):  
Olivier Rivoire ◽  
Kimberly A. Reynolds ◽  
Rama Ranganathan
Keyword(s):  
Amino Acid ◽  
Protein Function ◽  
Biological Properties ◽  
Protein Family ◽  
Structural Basis ◽  
Amino Acid Residues ◽  
Multiple Sequence ◽  
Global Pattern ◽  
Sector Analysis ◽  
Statistical Coupling

The essential biological properties of proteins - folding, biochemical activities, and the capacity to adapt - arise from the global pattern of interactions between amino acid residues. The statistical coupling analysis (SCA) is an approach to defining this pattern that involves the study of amino acid coevolution in an ensemble of sequences comprising a protein family. This approach indicates a functional architecture within proteins in which the basic units are coupled networks of amino acids termed sectors. This evolution-based decomposition has potential for new understandings of the structural basis for protein function, but requires broad further testing by the scientific community. To facilitate this, we present here the principles and practice of the SCA and introduce new methods for sector analysis in a python-based software package. We show that the pattern of amino acid interactions within sectors is linked to the divergence of functional lineages in a multiple sequence alignment - a model for how sector properties might be differentially tuned in members of a protein family. This work provides new tools for understanding the structural basis for protein function and for generally testing the concept of sectors as the principal functional units of proteins.

Biological Function and Chemistry of Endothelin. A Review

1999 ◽  
Vol 64 (8) ◽  
pp. 1211-1252 ◽  
Author(s):  
Jan Hlaváček ◽  
Renáta Marcová
Keyword(s):  
Biological Activity ◽  
Amino Acid ◽  
Biological Function ◽  
Biological Properties ◽  
Structural Basis ◽  
Amino Acid Residues ◽  
Snake Venoms ◽  
Vasoactive Peptides ◽  
Physico Chemical ◽  
Endothelin A

The first part of this review deals with the biosynthesis and a biological function of strongly vasoactive peptides named endothelins (ETs) including vasoactive intestinal contractor. Where it was useful, snake venoms sarafotoxins which are structural endothelin derivatives, were also mentioned. In the second part, an attention is paid to structural basis of the ETs biological activity, with respect to alterations of amino acid residues in the parent peptides modifying the conformation and consequently the physico-chemical and biological properties in corresponding ETs analogs. Special attention is focussed on the area of ETs receptors and their interaction with peptide and non peptide agonists and antagonists, important in designing selective inhibitors of ETs receptors potentially applicable as drugs in a medicine. A review with 182 references.

Evolutionary divergence and salinity-mediated selection in halophilic archaea

1997 ◽  
Vol 61 (1) ◽  
pp. 90-104
Author(s):  
P P Dennis ◽  
L C Shimmin
Keyword(s):  
Amino Acid ◽  
Tertiary Structure ◽  
Halophilic Archaea ◽  
Amino Acid Replacement ◽  
Evolutionary Divergence ◽  
Ionic Balance ◽  
Amino Acid Residues ◽  
Nucleotide Substitutions ◽  
Nonsynonymous Substitutions ◽  
Environmental Salinity

Halophilic (literally salt-loving) archaea are a highly evolved group of organisms that are uniquely able to survive in and exploit hypersaline environments. In this review, we examine the potential interplay between fluctuations in environmental salinity and the primary sequence and tertiary structure of halophilic proteins. The proteins of halophilic archaea are highly adapted and magnificently engineered to function in an intracellular milieu that is in ionic balance with an external environment containing between 2 and 5 M inorganic salt. To understand the nature of halophilic adaptation and to visualize this interplay, the sequences of genes encoding the L11, L1, L10, and L12 proteins of the large ribosome subunit and Mn/Fe superoxide dismutase proteins from three genera of halophilic archaea have been aligned and analyzed for the presence of synonymous and nonsynonymous nucleotide substitutions. Compared to homologous eubacterial genes, these halophilic genes exhibit an inordinately high proportion of nonsynonymous nucleotide substitutions that result in amino acid replacement in the encoded proteins. More than one-third of the replacements involve acidic amino acid residues. We suggest that fluctuations in environmental salinity provide the driving force for fixation of the excessive number of nonsynonymous substitutions. Tinkering with the number, location, and arrangement of acidic and other amino acid residues influences the fitness (i.e., hydrophobicity, surface hydration, and structural stability) of the halophilic protein. Tinkering is also evident at halophilic protein positions monomorphic or polymorphic for serine; more than one-third of these positions use both the TCN and the AGY serine codons, indicating that there have been multiple nonsynonymous substitutions at these positions. Our model suggests that fluctuating environmental salinity prevents optimization of fitness for many halophilic proteins and helps to explain the unusual evolutionary divergence of their encoding genes.

scholarly journals Human red blood cell Wright antigens: a genetic and evolutionary perspective on glycophorin A-band 3 interaction

Blood ◽  
1996 ◽  
Vol 87 (9) ◽  
pp. 3942-3947 ◽  
Author(s):  
CH Huang ◽  
ME Reid ◽  
SS Xie ◽  
OO Blumenfeld
Keyword(s):  
Amino Acid ◽  
Nonhuman Primates ◽  
Antigen Expression ◽  
Band 3 ◽  
Structural Basis ◽  
Antigenic Structure ◽  
Glycophorin A ◽  
Amino Acid Residues ◽  
Protein Protein Interaction ◽  
Human Red Blood Cells

The Wright (Wra/Wrb) blood group polymorphism is defined by an allelic change (Lys658Glu) in the band 3 protein; nevertheless, the Wrb antigen apparently requires glycophorin A (GPA) for surface presentation. To gain insight into the structural basis for this protein-protein interaction and delineate its relationship with Wrb antigen expression, we investigated GPA and band 3 sequence polymorphisms occurring in rare humans and nonhuman primates. The lack of GPA or amino acid residues 59 through 71 of GPA results in the absence of Wrb from human red blood cells (RBCs) exhibiting the MkMk, En(a-), or MiV phenotype. However, the SAT homozygous cells carried a Glu658 form of band 3 and a hybrid glycophorin with the entire GPA extramembrane domain from residues 1 through 71, yet expressed no Wrb antigen. This finding suggests that formation of the Wrb antigenic structure is dependent on protein folding and that the transmembrane junction of GPA is important in maintaining the required conformation. Comparative analyses of GPA and band 3 homologues led to the identification in the interacting regions of conserved and dispensable amino acid residues that correlated with the Wrb positive or negative status on nonhuman primates. In particular, the chimpanzee RBCs cells expressed Wrb and the Glu658 form of band 3, which is identical to humans, but their GPA contained the Gly rather than Arg residue at position 61. Taken together, the results suggest that (1) Arg61 of GPA and the proposed Arg61-Glu658 charge pair are not crucial for Wrb antigen exhibition and (2) the role of GPA for interaction with band 3, including Glu658, probably involves a number of amino acid residues located in the alpha-helical region and transmembrane junction.

HATODAS II – heavy-atom database system with potentiality scoring

2009 ◽  
Vol 42 (3) ◽  
pp. 540-544 ◽  
Author(s):  
Michihiro Sugahara ◽  
Yukuhiko Asada ◽  
Hiroki Shimada ◽  
Hideyuki Taka ◽  
Naoki Kunishima
Keyword(s):  
Amino Acid ◽  
Structure Prediction ◽  
Secondary Structure Prediction ◽  
Solvent Accessibility ◽  
Heavy Atom ◽  
Database System ◽  
Protein Crystals ◽  
Amino Acid Residues ◽  
Sequence Alignments ◽  
Homologous Proteins

HATODAS II is the second version of HATODAS (the Heavy-Atom Database System), which suggests potential heavy-atom reagents for the derivatization of protein crystals. The present expanded database contains 3103 heavy-atom binding sites, which is four times more than the previous version. HATODAS II has three new criteria to evaluate the feasibility of the search results: (1) potentiality scoring for the predicted heavy-atom reagents, (2) exclusion of the disordered amino acid residues based on the secondary structure prediction and (3) consideration of the solvent accessibility of amino acid residues from a homology model. In the point mutation option, HATODAS II suggests possible mutation sites into reactive amino acid residues such as Met, Cys and His, on the basis of multiple sequence alignments of homologous proteins. These new features allow the user to make a well informed decision as to the possible heavy-atom derivatization experiments of protein crystals.

scholarly journals CoRINs: A tool to compare residue interaction networks from homologous proteins and conformers

2020 ◽  
Author(s):  
Felipe V. da Fonseca ◽  
Romildo O. Souza Júnior ◽  
Marília V. A. de Almeida ◽  
Thiago D. Soares ◽  
Diego A. A. Morais ◽  
...  
Keyword(s):  
Protein Structure ◽  
Amino Acid ◽  
Conformational Changes ◽  
Protein Function ◽  
Protein Structures ◽  
Software Tool ◽  
Interaction Networks ◽  
Homologous Proteins ◽  
Residue Interaction ◽  
And Function

ABSTRACTMotivationA useful approach to evaluate protein structure and quickly visualize crucial physicochemical interactions related to protein function is to construct Residue Interactions Networks (RINs). By using this application of graphs theory, the amino acid residues constitute the nodes, and the edges represent their interactions with other structural elements. Although several tools that construct RINs are available, many of them do not compare RINs from distinct protein structures. This comparison can give valuable insights into the understanding of conformational changes and the effects of amino acid substitutions in protein structure and function. With that in mind, we present CoRINs (Comparator of Residue Interaction Networks), a software tool that extensively compares RINs. The program has an accessible and user-friendly web interface, which summarizes the differences in several network parameters using interactive plots and tables. As a usage example of CoRINs, we compared RINs from conformers of two cancer-associated proteins.AvailabilityThe program is available at https://github.com/LasisUFRN/CoRINs.

scholarly journals THE STRUCTURAL BASIS FOR BINDING OF COMPLEMENT BY IMMUNOGLOBULIN M

1974 ◽  
Vol 140 (4) ◽  
pp. 1117-1121 ◽  
Author(s):  
Mary M. Hurst ◽  
John E. Volanakis ◽  
Raymond B. Hester ◽  
Robert M. Stroud ◽  
J. Claude Bennett
Keyword(s):  
Amino Acid ◽  
Structural Features ◽  
Immunoglobulin M ◽  
Structural Basis ◽  
Amino Acid Residues ◽  
Amino Terminal ◽  
Terminal Domain ◽  
Carboxy Terminal Domain ◽  
Carboxy Terminal ◽  
Insight Into

An insight into the structural features of human IgM that are responsible for its capacity to bind the first component of complement (C) has been obtained by examining the ability of IgM subfragments to bind active C1 (C1). The smallest two fragments found to bind C1 were the major CNBr fragment of the Fc portion of IgM and the CH4 fragment of the carboxy-terminal domain. The smallest fragment which fixes C1 has a disaggregated mol wt of 6,800, consists of 60 residues, and contains no carbohydrate. Structural considerations and sequence overlaps suggest that the amino-terminal side of the CH4 domain (24 amino acid residues) might be responsible for fixing C1.

Sign in / Sign up

Export Citation Format

Share Document