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Projects / Programmes source: ARIS

Designed protein origami based receptors: functionalized designed protein nanostructures for the recognition of the selected targets

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Research activity

Code Science Field Subfield
1.05.00  Natural sciences and mathematics  Biochemistry and molecular biology   

Code Science Field
T360  Technological sciences  Biochemical technology 

Code Science Field
1.06  Natural Sciences  Biological sciences 
Keywords
protein nanostructures, coiled coils, functionalization, lectin, glycan, medicine
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (12)
no. Code Name and surname Research area Role Period No. of publications
1.  38163  PhD Jana Aupič  Biochemistry and molecular biology  Researcher  2019 - 2021  67 
2.  53421  Hana Esih  Biochemistry and molecular biology  Researcher  2021 - 2022  5 
3.  17915  PhD Helena Gradišar  Biotechnology  Head  2019 - 2022  130 
4.  06628  PhD Roman Jerala  Biochemistry and molecular biology  Researcher  2019 - 2022  1,190 
5.  37987  PhD Fabio Lapenta  Biochemistry and molecular biology  Researcher  2019 - 2020  53 
6.  17917  PhD Andreja Majerle  Biotechnology  Researcher  2019 - 2021  92 
7.  53665  Špela Malenšek  Biochemistry and molecular biology  Researcher  2021 - 2022  17 
8.  53353  Klemen Mezgec  Biochemistry and molecular biology  Researcher  2020 - 2022  3 
9.  38275  Anja Perčič    Technical associate  2019 - 2022  0 
10.  38337  PhD Žiga Strmšek  Biochemistry and molecular biology  Researcher  2019 - 2022  58 
11.  52006  Sara Vidmar  Biochemistry and molecular biology  Junior researcher  2019 - 2022  6 
12.  54954  Ana Županič    Technical associate  2021  0 
Organisations (1)
no. Code Research organisation City Registration number No. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  21,007 
Abstract
Proteins, encoded by the linear sequence of amino acids, represent versatile smart nanomaterials, performing countless functions such as the recognition, structural role, catalytic activity, movement and many others.  The design of protein assemblies that do not exist in nature has matured beyond the proof of the principles and is ready to face more complex challenges such as introduction of functions and the development of applications. New artificial proteins offers high rewards for medicine, technology and science.    Recently a pioneering strategy for the design of new types of a single-chain protein folds was devised in our group based on the sequential arrangement of concatenated coiled-coil dimer forming modules that self-assemble into a polyhedral cage with edges composed of rigid coiled-coil (CC) dimers. De novo designed polyhedral nanostructures represent a new type of modular folds that we named coiled-coil protein origami (CCPO). Due to their robustness and versatile designable shapes and properties, designed CCPO posess a great potential for numerous biomedical applications for diagnostics, prevention and therapy.      One of the outstanding opportunities is to exploit the CCPOs with designed architecture as the scaffolds for functionalization with biospecific recognition molecules that recognize the selected targets. CCPOs may serve as an attractive platform for positioning functional groups into the defined position in order to embed the required functionality.     Lectins are proteins that can act as biospecific recognition molecules for different glycans. One such example is recognition of the glycosylation pattern of a prostate-specific antigen (PSA), a biomarker of a prostate cancer (PCa). Although the analysis of glycans by lectins has some limitations (low specificity, low affinity), the main advantage of using lectins is the fact that lectins can be applied for interaction with glycans still attached to proteins or even intact cells. However, glycan-protein interactions play a pivotal role in viral and bacterial infections, cell adhesion, and the differentiation and progression of various diseases and are thus of great interest for many diagnostic and therapeutic applications.   The central inovative idea of this project proposal is ti design and produce trigonal-shaped CCPOs, functionalized by different lectins that can act as glycans recognition sensor. This proposal aims to apply our expertise in the design of polypeptide CCPO nanostructures as well as expertise of our collaborator on the fields of glycomics and cancer diagnostics, on the requirements of the medicine to establish the assay based on lectin-glycan interaction for screening or diagnostics. The expected results of the project will represent an important milestone demonstrating the site-specific functionalization and application for the designed polypeptide nanostructures CCPOs.    The main goal of this project is to design artificial glycan receptors with the defined stoichiometry and geometric arrangement of binding sites by testing different strategies for the introduction of functional sites into the CCPO scaffolds. An increased valence of the artificial receptor (e.g. trimeric lectins) is expected to strongly increase the affinity by introduction of one lectin domain at two or three vertices/edges of CCPO or specificity, such as by expression of two or three different lectins at vertices/edges of the CCPO. The aim of the project is to design and test if the prospective cancer biomarker lectins have more specific and stronger binding to glycan-containing targets (molecules or cell lines) when incorporated into the CCPO scaffold. It is expected that the integration of medically important domains into the CCPO structure can be used in medicine for screening or diagnosis.
Significance for science
Despite advances in computational modeling of protein nanostructures and successes of protein engineering in the recent years, the de novo design of proteins with new in the nature unobserved folds is still challenging. Proteins have significantly larger functional potential as molecular machines than nucleic acids, which have also been used to design various nanoscale shapes. Recently a pioneering strategy for the design of new types of a single-chain protein folds was devised in our group based on the sequential arrangement of concatenated coiled-coil dimer forming modules that self-assemble into a polyhedral cage (tetrahedron, square pyramid, bipyramid or triangle) with edges composed of rigid coiled-coil. De novo designed polyhedral nanostructures represent an new, attractive type of modular folds that we named coiled-coil protein origami (CCPO). Due to their versatile designable shapes and properties, designed CCPO might be potentially used for numerous biomedical applications for diagnostics, prevention and therapy. The project aims to develop the basic principles for expanding the boundaries of the CCPO nanostructures functionality, bridging towards various applications. We will provide the proof-of-concept results relating to the functionalization of designed CCPO nanostructures. We will demonstrate the introduction of the selected functional protein domains at the selected positions of the nanostructure. Introducing lectins, as biospecific recognition molecules for the selected target, we will establish the assay for detection of different glycans. Further, in collaboration with lectinomics expert we will apply an assay for detection of a prostate-specific antigen (PSA), a biomarker of prostate cancer (PCa). We can expect to generate potentially very useful intellectual property and publications in high ranked journals, similar to those that the PI had demonstrated in recent years (Nature Biotech., 2017; JASC, 2017; Curr.Op.Chem.Biol., 2017; Nature Comm., 2016; Adv.Exp.Med.Biol., 2016; Nature Chem. Biol., 2013).   Our interdisciplinary approach combining the expertise from synthetic biology, biochemistry and medicine represents an innovative and original contribution in these very competitive disciplines. Results of the project will lead to new scientific knowledge and will be of great interest for many diagnostic and therapeutic applications in medicine, as well as for a broader scientific audience.
Significance for the country
Despite advances in computational modeling of protein nanostructures and successes of protein engineering in the recent years, the de novo design of proteins with new in the nature unobserved folds is still challenging. Proteins have significantly larger functional potential as molecular machines than nucleic acids, which have also been used to design various nanoscale shapes. Recently a pioneering strategy for the design of new types of a single-chain protein folds was devised in our group based on the sequential arrangement of concatenated coiled-coil dimer forming modules that self-assemble into a polyhedral cage (tetrahedron, square pyramid, bipyramid or triangle) with edges composed of rigid coiled-coil. De novo designed polyhedral nanostructures represent an new, attractive type of modular folds that we named coiled-coil protein origami (CCPO). Due to their versatile designable shapes and properties, designed CCPO might be potentially used for numerous biomedical applications for diagnostics, prevention and therapy. The project aims to develop the basic principles for expanding the boundaries of the CCPO nanostructures functionality, bridging towards various applications. We will provide the proof-of-concept results relating to the functionalization of designed CCPO nanostructures. We will demonstrate the introduction of the selected functional protein domains at the selected positions of the nanostructure. Introducing lectins, as biospecific recognition molecules for the selected target, we will establish the assay for detection of different glycans. Further, in collaboration with lectinomics expert we will apply an assay for detection of a prostate-specific antigen (PSA), a biomarker of prostate cancer (PCa). We can expect to generate potentially very useful intellectual property and publications in high ranked journals, similar to those that the PI had demonstrated in recent years (Nature Biotech., 2017; JASC, 2017; Curr.Op.Chem.Biol., 2017; Nature Comm., 2016; Adv.Exp.Med.Biol., 2016; Nature Chem. Biol., 2013).   Our interdisciplinary approach combining the expertise from synthetic biology, biochemistry and medicine represents an innovative and original contribution in these very competitive disciplines. Results of the project will lead to new scientific knowledge and will be of great interest for many diagnostic and therapeutic applications in medicine, as well as for a broader scientific audience.
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