Thrombospondin repeat (TSR) domains which are prevalent in the human genome are known to bind many partners <i>in vivo</i>. A total of 301 TSR domains are currently recognized by the UNIPROT database. Each TSR domain has a characteristic TRP-ladder and a series of conserved disulfide bonds. No study has been performed to determine if structural variations in the TSR domains exist broadly or categorize variations in the TRP-ladder that could potentially contribute to differences in function. Thus, this work was performed to investigate the structural patterns of the TSR domains in the human genome, determine if any common variations exits, and evaluate if functional properties could be assigned to the variations. Homology models of all 301 currently identified TSR domains and three sequences suspected to be TSR domains were developed using Phyre<sup>2</sup> homology modeling server and evaluated. Characterization of the ladder sequences revealed three broad groups of ladder types that correlated to a specific protein family. Several TSR domains in the thrombospondin family of proteins were demonstrated to contain insertions into the canonical fold. At least two of these insertions are polybasic regions and contain almost 50 residues. Modeling results of this work suggests that there are at least 304 TSR domains and that several of the reported sequences have minor corrections to the specific residues which should be included in the labeled TSR domain on the UNIPROT database. MD simulations will be performed on several domains to determine flexibility and will be discussed. The results of this work will contribute to updates to the UNIPROT database to clarify the TSR domains for the human genome. Additionally, structural biologist and protein chemists will learn new details about the TSR domain containing superfamily of proteins to assist in discovery of structure function relationships of the TSR domain containing superfamily.

Modeling, characterization, and classification of human thrombospondin type-1 like domains: Evidence for TRP ladder functionalization based on ladder type?

ACS Spring Meeting 2021

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