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Proteinase Inhibitors: An Overview of their Structure and Possible Function in the Acute Phase
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Superfamily — Proteins that are suspected to be derived from a common ancestral gene are members of the same superfamily. This definition is very arbitrary, but usually applies to proteins with identities of more than 30%. Exon shuffling during the course of evolution of a protein can blur the superfamily distinction, since domains from one ancestor have sometimes combined with domains from an unrelated gene. Nevertheless, the superfamily distinction is usually relatively obvious with mammalian proteinase inhibitors. Members of a superfamily often possess comparable activities, so that if a protein is only 25% identical to another one, but the two share a common activity, they are probably descended from a common ancestor. The genomic equivalent of a protein superfamily is the supergene family.
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Non-homologous recombination methods have also been developed to produce chimeric proteins via recombination of parental sequences which are non-homologous. Non-homologous parental sequences imply that they share very little sequence identity. Such non-homologous sequences cannot be recombined using the above-mentioned homologous recombination methods. Exon shuffling is the one of the non-homologous recombination methods developed by Kolkman and Stemmer (Kolkman and Stemmer, 2001). This method essentially requires mixing of exons from different protein genes via recombination at the intervening regions known as introns. Chimeric protein will exhibit the features of all the recombining exons (Kolkman and Stemmer, 2001). Further, diversity can be inculcated in these chimeras by insertion, deletion, or substitution during the recombination event. Few other non-homologous recombination techniques such as incremental truncation for the creation of hybrid enzymes (ITCHY) (Ostermeier et al., 1999), sequence homology independent protein recombination (SHIPREC) (Sieber et al., 2001), Degenerate Homo-duplex Recombination (DHR) (Coco et al., 2002), Random Multi-recombinant PCR (RM-PCR) (Tsuji et al., 2001), golden gate shuffling (GGS) Recombination (Engler et al., 2009), Integron (Bikard et al., 2010), Y-ligation-based shuffling (YLBS) (Kitamura et al., 2002) have also been developed to generate chimeric proteins with novel functionalities.
Structure/Function Relationships of t-PA
Published in Cornelis Kluft, Tissue-Type Plasminogen Activator (t-PA): Physiological and Clinical Aspects, 1988
The wide distribution of certain domains, also outside the serine protease family, suggests that exon shuffling has occurred frequently during the evolution of the proteins.154 Based on this assumption and by determining the homologies between the domains, Patthy proposed an interesting evolutionary scenario for the assembly of the noncatalytic regions of proteases (Figure 3)154 According to this model, t-PA (as the other proteases) originates from an ancestral trypsin-like protease (P), having already a signal peptide and a zymogen peptide domain. After insertion of a growth factor domain (GA), a fibrinolytic enzyme diverged from a coagulation enzyme, and a kringle domain (K) was inserted in the former one. Then a plasminogen activator diverged from plasminogen t-PA diverged from u-PA, a finger domain (F) was inserted, and a second kringle arose by gene duplication.
Challenges related to the immunogenicity of parenteral recombinant proteins: Underlying mechanisms and new approaches to overcome it
Published in International Reviews of Immunology, 2018
Fatemeh Faraji, Zahra Karjoo, Maryam Vakili Moghaddam, Sahel Heidari, Reza Zolfaghari Emameh, Reza Falak
Different approaches have been introduced to modify andTable 1 diminish the immunogenicity of therapeutic protein products (Table 1). Different strategies such as direct modification of the protein through PEGylation and/or glycosylation methods to cover immunogenic epitopes, whereby decreasing its recognition by the immune system, changing MHC II anchor residues of immunodominant determinants to prevent presentation, applications of methods to induce tolerance in the immune system to the therapeutic protein, removing immunogenic epitopes via site-specific mutagenesis, exon shuffling, and humanization of monoclonal antibodies were considered up to now.12,76