The coagulation Factor XIII (FXIII) A subunit activation peptide directs the evolution of FXIIIA as a proteolytically activated dimeric molecule

A. Biswas, S. Singh, V. Ivaskevicius , J. Oldenburg (Bonn, Germany)

Bleeding disorders, coagulation and fibrinolytic factors
Date: 17.02.2017,
Time: 17:15 - 18:15

Objective: To trace the evolutionary origins of Factor XIII (FXIIIA) subunit activation peptide (FXIII-AP) and its importance in the speciation events leading to generation of FXIIIA subunit dimeric molecule.

Methods: Nucleotide and amino acid sequences of coagulation FXIIIA subunit, the activation peptide itself and of other Transglutaminase paralogues were downloaded from pubmed. Sequences were manually curated to eliminate redundancy and reduce error rates arising from partial/incorrect sequences. After generating high quality multiple alignments phylogenetic analysis was performed for both types of sequences on the GUI platform of MEGAversion7. On a structural level all zymogenic and activated forms of FXIIIA and other known TGs were downloaded from protein structure database. The TGs for whom no structures were available, threading based structures were generated on the ITASSER server. Structure alignment and visual comparative analysis was performed on the YASARA platform.

Results: The FXIII-AP has evolved from the membrane anchorage region of TGM1 as a result of a loss of function deletion. The evolution of the FXIII-AP has directed the evolution of FXIIIA subunit as a functionally similar but structurally distinct (dimer) class of enzyme within the transglutaminases. The N terminal region of the FXIII-AP shows a higher substitution rate than the C-terminal part (which is highly conserved) indicating that while the C-terminal part is structural in function, the N-terminal part is meant for protein-protein interaction. Cross conservation analysis suggests that part of the activation peptide originates from a sequence on the beta sandwich domain of TGM5 and Erythrocyte membrane protein band 4.2 and moves through TGM1 to FXIIIA through a series of gain of function and loss of function mutations.

Conclusion: FXIII-AP is not only an important region for the activation of FXIIIA subunit; it has also played a very important role in the specialized evolution of FXIIIA.