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ORIGINAL RESEARCH article

Front. Bioinform.
Sec. Evolutionary Bioinformatics
Volume 5 - 2025 | doi: 10.3389/fbinf.2025.1491735
This article is part of the Research Topic Evolution of Short Genomic Regions: Discoveries, Methods, and Challenges View all articles

Divergent evolution of low-complexity regions in the vertebrate CPEB protein family

Provisionally accepted
Serena Vaglietti Serena Vaglietti Stefania Boggio Bozzo Stefania Boggio Bozzo Mirella Ghirardi Mirella Ghirardi Ferdinando Fiumara Ferdinando Fiumara *
  • Department of Neuroscience, School of Medicine, University of Turin, Turin, Piedmont, Italy

The final, formatted version of the article will be published soon.

    The cytoplasmic polyadenylation element-binding proteins (CPEBs) are a family of translational regulators involved in multiple biological processes, including memory-related synaptic plasticity. In vertebrates, four paralogous genes (CPEB1-4) encode proteins with phylogenetically conserved C-terminal RNA-binding domains and variable N-terminal regions (NTRs). The CPEB NTRs are characterized by low-complexity regions (LCRs), including homopolymeric amino acid repeats (AARs), and have been identified as mediators of liquid-liquid phase separation (LLPS) and prion-like aggregation. After their appearance following gene duplication, the four paralogous CREB proteins functionally diverged in terms of activation mechanisms and modes of mRNA binding.The paralog-specific NTRs may have contributed substantially to such functional diversification but their evolutionary history remains largely unexplored. Here, we traced the evolution of vertebrate CPEBs and their LCRs/AARs in terms of primary sequence composition, complexity, repetitiveness, and their possible functional impact on LLPS and prion-likeness. We initially defined these composition-and function-related quantitative parameters for the four human CPEB paralogs and then systematically analyzed their evolutionary variation across more than 500 species belonging to nine major clades of different stem age, from Chondrichthyes to Euarchontoglires, along the vertebrate lineage. We found that the four CPEB proteins display highly divergent, paralog-specific evolutionary trends in composition-and function-related parameters, involving primarily their LCRs/AARs, largely related to clade stem ages. These findings shed new light on the molecular and functional evolution of LCRs in the CPEB protein family, in both quantitative and qualitative terms, highlighting the emergence of CPEB2 as a proline-rich prion-like protein in younger vertebrate clades, including Primates.

    Keywords: cytoplasmic polyadenylation element binding protein, CPEB proteins, liquid-liquid phase separation (LLPS), Prion-like proteins, Low-complexity regions (LCRs), homopolymeric amino acid repeats, divergent evolution, Paralogous proteins

    Received: 05 Sep 2024; Accepted: 28 Jan 2025.

    Copyright: © 2025 Vaglietti, Boggio Bozzo, Ghirardi and Fiumara. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Ferdinando Fiumara, Department of Neuroscience, School of Medicine, University of Turin, Turin, 10124, Piedmont, Italy

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