Multimeric and polymeric proteins are large biomacromolecules consisting of multiple protein molecules as their monomeric units, connected through covalent or non-covalent bonds. Genetic modification and post-translational modifications (PTMs) of proteins offer alternative strategies for designing and creating multimeric and polymeric proteins. Multimeric proteins are commonly prepared by genetic modification, whereas polymeric proteins are usually created through PTMs. There are two methods that can be applied to create polymeric proteins: self-assembly and crosslinking. Self-assembly offers a spontaneous reaction without a catalyst, while the crosslinking reaction offers some catalyst options, such as chemicals and enzymes. In addition, enzymes are excellent catalysts because they provide site-specificity, rapid reaction, mild reaction conditions, and activity and functionality maintenance of protein polymers. However, only a few enzymes are applicable for the preparation of protein polymers. Most of the other enzymes are effective only for protein conjugation or labeling. Here, we review novel and applicable strategies for the preparation of multimeric proteins through genetic modification and self-assembly. We then describe the formation of protein polymers through site-selective crosslinking reactions catalyzed by enzymes, crosslinking reactions of non-natural amino acids, and protein-peptide (SpyCatcher/SpyTag) interactions. Finally, we discuss the potential applications of these protein polymers.
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