scholarly journals The Generation of New Protein Functions by the Combination of Domains

Structure ◽  
2007 ◽  
Vol 15 (1) ◽  
pp. 85-99 ◽  
Author(s):  
Matthew Bashton ◽  
Cyrus Chothia
Keyword(s):  
Protein Functions ◽  
New Protein

scholarly journals Laboratory-Directed Protein Evolution

2005 ◽  
Vol 69 (3) ◽  
pp. 373-392 ◽  
Author(s):  
Ling Yuan ◽  
Itzhak Kurek ◽  
James English ◽  
Robert Keenan
Keyword(s):  
Protein Evolution ◽  
Selective Pressure ◽  
Evolutionary Potential ◽  
Effective Strategies ◽  
Scientific Disciplines ◽  
Wide Range ◽  
Protein Functions ◽  
Evolution Of Proteins ◽  
Efficient Screening ◽  
New Protein

SUMMARY Systematic approaches to directed evolution of proteins have been documented since the 1970s. The ability to recruit new protein functions arises from the considerable substrate ambiguity of many proteins. The substrate ambiguity of a protein can be interpreted as the evolutionary potential that allows a protein to acquire new specificities through mutation or to regain function via mutations that differ from the original protein sequence. All organisms have evolutionarily exploited this substrate ambiguity. When exploited in a laboratory under controlled mutagenesis and selection, it enables a protein to “evolve” in desired directions. One of the most effective strategies in directed protein evolution is to gradually accumulate mutations, either sequentially or by recombination, while applying selective pressure. This is typically achieved by the generation of libraries of mutants followed by efficient screening of these libraries for targeted functions and subsequent repetition of the process using improved mutants from the previous screening. Here we review some of the successful strategies in creating protein diversity and the more recent progress in directed protein evolution in a wide range of scientific disciplines and its impacts in chemical, pharmaceutical, and agricultural sciences.

scholarly journals Accurately positioning functional residues with robotics-inspired computational protein design

2021 ◽  
Author(s):  
Cody Krivacic ◽  
Kale Kundert ◽  
Xingjie Pan ◽  
Roland A Pache ◽  
Lin Liu ◽  
...  
Keyword(s):  
Protein Design ◽  
Active Sites ◽  
Peptide Fragments ◽  
Loop Conformations ◽  
Protein Functions ◽  
Protein Backbones ◽  
Design Protocol ◽  
New Protein ◽  
Active Site Region ◽  
Local Protein

Accurate positioning of functional residues is critical for the design of new protein functions, but has remained difficult because of the prevalence of irregular local geometries in active sites. Here we introduce two computational methods that build local protein geometries from sequence with atomic accuracy: fragment kinematic closure (FKIC) and loophash kinematic closure (LHKIC). FKIC and LHKIC integrate two approaches: robotics-inspired kinematics of protein backbones and insertion of peptide fragments, and show up to 140-fold improvements in native-like predictions over either approach alone. We then integrate these methods into a new design protocol, pull-into-place (PIP), to position functionally important sidechains via design of new structured loop conformations. We validate PIP by remodeling a sizeable active site region in an enzyme and confirming the engineered new conformations of two designs with crystal structures. The described methods can be applied broadly to the design of many new protein geometries and functions.

scholarly journals Antimicrobial functions of lactoferrin promote genetic conflicts in ancient primates and modern humans

2016 ◽  
Author(s):  
Matthew F. Barber ◽  
Zev N. Kronenberg ◽  
Mark Yandell ◽  
Nels C. Elde
Keyword(s):  
Positive Selection ◽  
Pathogenic Bacteria ◽  
Modern Human ◽  
Human Populations ◽  
Human Genetic Variation ◽  
Cationic Protein ◽  
Protein Functions ◽  
Genetic Conflicts ◽  
New Protein

Lactoferrin is a multifunctional mammalian immunity protein that limits microbial growth through sequestration of nutrient iron. Additionally, lactoferrin possesses cationic protein domains that directly bind and inhibit diverse microbes. The implications for these dual functions on lactoferrin evolution and genetic conflicts with pathogens remain unclear. Here we show that lactoferrin has been subject to recurrent episodes of positive selection during primate divergence predominately at antimicrobial peptide surfaces consistent with long-term antagonism by pathogens. An abundant lactoferrin polymorphism in human populations and Neanderthals also exhibits signatures of positive selection across primates, linking ancient host-microbe conflicts to modern human genetic variation. Rapidly evolving sites in lactoferrin further correspond to molecular interfaces with pathogenic bacteria causing meningitis, pneumonia, and sepsis. Because microbes actively target lactoferrin to acquire iron, we propose that the emergence of antimicrobial activity provided a pivotal mechanism of adaptation sparking evolutionary conflicts via acquisition of new protein functions.

Post-Translation Regulation of Influenza Virus Replication

2020 ◽  
Vol 7 (1) ◽  
pp. 167-187
Author(s):  
Anthony R. Dawson ◽  
Gary M. Wilson ◽  
Joshua J. Coon ◽  
Andrew Mehle
Keyword(s):  
Influenza Virus ◽  
Protein Function ◽  
Translation Regulation ◽  
Host Use ◽  
Host Proteins ◽  
Post Translational Modifications ◽  
Cellular Factors ◽  
Protein Functions ◽  
Influenza Virus Replication ◽  
New Protein

Influenza virus exploits cellular factors to complete each step of viral replication. Yet, multiple host proteins actively block replication. Consequently, infection success depends on the relative speed and efficacy at which both the virus and host use their respective effectors. Post-translational modifications (PTMs) afford both the virus and the host means to readily adapt protein function without the need for new protein production. Here we use influenza virus to address concepts common to all viruses, reviewing how PTMs facilitate and thwart each step of the replication cycle. We also discuss advancements in proteomic methods that better characterize PTMs. Although some effectors and PTMs have clear pro- or antiviral functions, PTMs generally play regulatory roles to tune protein functions, levels, and localization. Synthesis of our current understanding reveals complex regulatory schemes where the effects of PTMs are time and context dependent as the virus and host battle to control infection.

scholarly journals Exploring modular allostery via interchangeable regulatory domains

2018 ◽  
Vol 115 (12) ◽  
pp. 3006-3011 ◽  
Author(s):  
Yifei Fan ◽  
Penelope J. Cross ◽  
Geoffrey B. Jameson ◽  
Emily J. Parker
Keyword(s):  
Catalytic Domain ◽  
Chorismate Mutase ◽  
Ligand Specificity ◽  
Diverse Range ◽  
Regulatory Domains ◽  
Protein Functions ◽  
Catalytically Active ◽  
Allosteric Mechanisms ◽  
Common Architecture ◽  
New Protein

Most proteins comprise two or more domains from a limited suite of protein families. These domains are often rearranged in various combinations through gene fusion events to evolve new protein functions, including the acquisition of protein allostery through the incorporation of regulatory domains. The enzyme 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS) is the first enzyme of aromatic amino acid biosynthesis and displays a diverse range of allosteric mechanisms. DAH7PSs adopt a common architecture with a shared (β/α)8 catalytic domain which can be attached to an ACT-like or a chorismate mutase regulatory domain that operates via distinct mechanisms. These respective domains confer allosteric regulation by controlling DAH7PS function in response to ligand Tyr or prephenate. Starting with contemporary DAH7PS proteins, two protein chimeras were created, with interchanged regulatory domains. Both engineered proteins were catalytically active and delivered new functional allostery with switched ligand specificity and allosteric mechanisms delivered by their nonhomologous regulatory domains. This interchangeability of protein domains represents an efficient method not only to engineer allostery in multidomain proteins but to create a new bifunctional enzyme.

scholarly journals New protein functions in yeast chromosome VIII

1995 ◽  
Vol 4 (11) ◽  
pp. 2424-2428 ◽  
Author(s):  
Christos Ouzounis ◽  
Peer Bork ◽  
Georg Casari ◽  
Chris Sander
Keyword(s):  
Yeast Chromosome ◽  
Protein Functions ◽  
New Protein ◽  
Chromosome Viii

scholarly journals Computational design of structured loops for new protein functions

2019 ◽  
Vol 400 (3) ◽  
pp. 275-288 ◽  
Author(s):  
Kale Kundert ◽  
Tanja Kortemme
Keyword(s):  
Protein Design ◽  
Protein Function ◽  
Structure Prediction ◽  
Computational Design ◽  
Loop Structure ◽  
Functional Sites ◽  
Loop Design ◽  
Routine Design ◽  
Protein Functions ◽  
New Protein

Abstract The ability to engineer the precise geometries, fine-tuned energetics and subtle dynamics that are characteristic of functional proteins is a major unsolved challenge in the field of computational protein design. In natural proteins, functional sites exhibiting these properties often feature structured loops. However, unlike the elements of secondary structures that comprise idealized protein folds, structured loops have been difficult to design computationally. Addressing this shortcoming in a general way is a necessary first step towards the routine design of protein function. In this perspective, we will describe the progress that has been made on this problem and discuss how recent advances in the field of loop structure prediction can be harnessed and applied to the inverse problem of computational loop design.

scholarly journals Synthetic protein interactions reveal a functional map of the cell

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lisa K Berry ◽  
Guðjón Ólafsson ◽  
Elena Ledesma-Fernández ◽  
Peter H Thorpe
Keyword(s):  
Protein Interactions ◽  
Protein Localization ◽  
Eukaryotic Cells ◽  
Protein Protein Interactions ◽  
Yeast Saccharomyces Cerevisiae ◽  
Synthetic Protein ◽  
Protein Functions ◽  
Functional Map ◽  
Cellular Compartments ◽  
New Protein

To understand the function of eukaryotic cells, it is critical to understand the role of protein-protein interactions and protein localization. Currently, we do not know the importance of global protein localization nor do we understand to what extent the cell is permissive for new protein associations – a key requirement for the evolution of new protein functions. To answer this question, we fused every protein in the yeast Saccharomyces cerevisiae with a partner from each of the major cellular compartments and quantitatively assessed the effects upon growth. This analysis reveals that cells have a remarkable and unanticipated tolerance for forced protein associations, even if these associations lead to a proportion of the protein moving compartments within the cell. Furthermore, the interactions that do perturb growth provide a functional map of spatial protein regulation, identifying key regulatory complexes for the normal homeostasis of eukaryotic cells.

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