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The evolution of multimeric protein assemblages.

ABSTRACT: Although the mechanisms by which complex cellular features evolve constitute one of the great unsolved problems of evolutionary biology, it is clear that the emergence of new protein-protein interactions, often accompanied by the diversification of duplicate genes, is involved. Using information on the levels of protein multimerization in major phylogenetic groups as a guide to the patterns that must be explained and relying on results from population-genetic theory to define the relative plausibility of alternative evolutionary pathways, a framework for understanding the evolution of dimers is developed. The resultant theory demonstrates that the likelihoods of alternative pathways for the emergence of protein complexes depend strongly on the effective population size. Nonetheless, it is equally clear that further advancements in this area will require comparative studies on the fitness consequences of alternative monomeric and dimeric proteins.

SUBMITTER: Lynch M

PROVIDER: S-EPMC3339316 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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The evolution of multimeric protein assemblages.

Lynch Michael M

Molecular biology and evolution 20111205 5

Although the mechanisms by which complex cellular features evolve constitute one of the great unsolved problems of evolutionary biology, it is clear that the emergence of new protein-protein interactions, often accompanied by the diversification of duplicate genes, is involved. Using information on the levels of protein multimerization in major phylogenetic groups as a guide to the patterns that must be explained and relying on results from population-genetic theory to define the relative plausi ...[more]

PMID: 22144639

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Project description:Recombinant protein therapeutics have increased in number and frequency since the introduction of human insulin, 25 years ago. Presently, proteins and peptides are commonly used in the clinic. However, the incorporation of peptides into clinically approved nanomedicines has been limited. Reasons for this include the challenges of decorating pharmaceutical-grade nanoparticles with proteins by a process that is robust, scalable, and cost-effective. As an alternative to covalent bioconjugation between a protein and nanoparticle, we report that biologically active proteins may themselves mediate the formation of small multimers through steric stabilization by large protein polymers. Unlike multistep purification and bioconjugation, this approach is completed during biosynthesis. As proof-of-principle, the disintegrin protein called vicrostatin (VCN) was fused to an elastin-like polypeptide (A192). A significant fraction of fusion proteins self-assembled into multimers with a hydrodynamic radius of 15.9 nm. The A192-VCN fusion proteins compete specifically for cell-surface integrins on human umbilical vein endothelial cells (HUVECs) and two breast cancer cell lines, MDA-MB-231 and MDA-MB-435. Confocal microscopy revealed that, unlike linear RGD-containing protein polymers, the disintegrin fusion protein undergoes rapid cellular internalization. To explore their potential clinical applications, fusion proteins were characterized using small animal positron emission tomography (microPET). Passive tumor accumulation was observed for control protein polymers; however, the tumor accumulation of A192-VCN was saturable, which is consistent with integrin-mediated binding. The fusion of a protein polymer and disintegrin results in a higher intratumoral contrast compared to free VCN or A192 alone. Given the diversity of disintegrin proteins with specificity for various cell-surface integrins, disintegrin fusions are a new source of biomaterials with potential diagnostic and therapeutic applications.

Dataset Information

The evolution of multimeric protein assemblages.

Publications

The evolution of multimeric protein assemblages.

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