Repeat protein Function Refinement, Annotation and Classification of Topologies

Project Information

REFRACT

Grant agreement ID: 823886

DOI

10.3030/823886

Project closed

EC signature date 26 October 2018

Start date 1 January 2019

End date 30 June 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 2 392 000,00

EU contribution

€ 2 226 400,00

Coordinated by

UNIVERSITA DEGLI STUDI DI PADOVA
Italy

Periodic Reporting for period 2 - REFRACT (Repeat protein Function Refinement, Annotation and Classification of Topologies)

Reporting period: 2022-07-01 to 2024-06-30

Summary of the context and overall objectives of the project

Tandem repeat proteins (TRPs) exhibit considerable diversity, ranging from simple homorepeats detectable by their lack of sequence complexity to cryptic repeats of up to 40 residues per unit and even entire domains. Typically, repeat protein sequences fold into a modular structure characterized by the repetition of identical structural units. These sequences are ubiquitous in genomes and are overrepresented in complex organisms—for instance, they are present in nearly a third of human proteins. Tandem repeat proteins have found their ideal functional niche in biological pathways that require rapid evolution, such as host-pathogen interactions, and have played a crucial role in the evolution of eukaryotes by compensating for their lower mutation rates. Moreover, numerous studies over the past decade have linked repeat proteins to human diseases and emerging infectious threats, underscoring the critical nature of their functions.

The REFRACT consortium was established to address major challenges in the field of tandem repeat proteins, including benchmarking and enhancing existing methods for detecting repeat regions and deepening the understanding of their functional mechanisms and evolution. As an international effort, REFRACT aimed to expand knowledge on the mechanisms of tandem repeat protein function and evolution by establishing a common classification and best practices. The consortium achieved these objectives through several key initiatives: benchmarking existing methods and defining their use-cases; coordinating efforts to analyze the roles of repeat proteins in biological pathways and organism evolution; providing detailed descriptions of their mechanisms; and developing and characterizing a widely accepted classification of repeat proteins based on sequence and structure. Starting with state-of-the-art computational tools and databases available at the time, REFRACT leveraged the complementary expertise of institutions across Europe and Latin America to drive a new level of characterization for tandem repeat proteins.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The REFRACT project has pushed the boundaries of current scientific understanding and technology in the field of TRPs. The first outcomes centered on developing and refining methodologies for detecting TRPs, understanding their functional roles, and integrating these insights into key bioinformatics resources. The project successfully developed novel tools and methodologies, such as Tally-2.0 TRAL 2.0 REP2, WebSTR and STRPsearch, which have advanced the benchmarking of TRP detection, classification and analysis. These tools have significantly contributed to the functional annotation of TRPs, with new data integrated into established databases like RepeatsDB, Pfam, and InterPro, thereby enhancing the accuracy and usability of these critical resources.

In addition to these scientific and technological advances, the project has also made significant progress in database and resource integration. This was achieved through the deployment of APIs for RepeatsDB and the cross-linking of TRP data into major bioinformatics platforms, facilitating broader access and enabling both manual and automated curation efforts across multiple platforms. Furthermore, the project has been proactive in disseminating its results through high-impact publications, international conferences, and collaborative events. These efforts were complemented by extensive training activities, particularly in Latin America, which have helped to strengthen global research networks focused on TRPs. This not only contributed to capacity building in underrepresented regions but also fostered interdisciplinary collaboration.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The adoption of a community consensus definition for Structured Tandem Repeats Proteins and the integration of cutting-edge AI tools like AlphaFold into TRP research have pushed the boundaries of current scientific understanding. These efforts have yielded new insights into the role of TRPs in protein-protein interactions, RNA/DNA binding, and host-pathogen interactions, which are anticipated to inform future research across both basic and applied life sciences.
Looking ahead, the project is expected to continue enhancing TRP annotations in major bioinformatics databases, further refining tools for TRP detection and classification. The ongoing integration of TRP data into core-data resources is projected to result in more accurate and comprehensive annotations, supporting a wide range of biological research.
Beyond the scientific community, the REFRACT project has raised awareness of the importance of TRPs in life sciences and contributed to the development of new strategies for understanding diseases and potential therapeutic interventions. The project’s training and dissemination activities have also had a positive impact on scientific capacity in Latin America, promoting international collaboration and innovation in the study of non-globular proteins.

Overview of STRP features. Single protein chain definition.

The challenge of Tandem Repeat Proteins

Tandem Repeat Protein Dichotomies

Examples of tandem repeat protein functions

The REFRACT consortium at the 3rd All Hands Meeting in Padova, 5-7 October 2022