Maintenance of a protein structure in the dynamic evolution of TIMPs over 600 million years

Abstract

Deciphering the events leading to protein evolution represents a challenge, especially for protein families showing complex evolutionaryhistory. Amongthem,TIMPs represent anancient eukaryoticprotein family widelydistributed in the animal kingdom.They are knowntocontrol the turnoverof the extracellularmatrix andare considered toarise early duringmetazoan evolution, arguably tuning essential features of tissue andepithelialorganization. To probe the structure andmolecular evolution of TIMPs withinmetazoans,we report themining and structural characterization of a large data set of TIMPs over approximately 600 Myr. The TIMPs repertoirewas explored starting from the Cnidaria phylum, coeval with the origins of connective tissue, to great apes and humans. Despite dramatic sequence differences compared with highest metazoans, the ancestral proteins displayed the canonical TIMP fold. Only small structural changes, represented by an a-helix located in the N-domain, have occurred over the evolution. Both the occurrence of such secondary structure elements and the relative solvent accessibility of the corresponding residues in the three-dimensional structures raises the possibility that these sites represent unconserved element prone to accept variations.