Crystal structure and mutational analysis of the human TRIM7 B30.2 domain provide insights into the molecular basis of its binding to glycogenin-1

Tripartite motif (TRIM)7 is an E3 ubiquitin ligase that was first identified through its interaction with glycogenin-1 (GN1), the autoglucosyltransferase that initiates glycogen biosynthesis. A growing body of evidence indicates that TRIM7 plays an important role in cancer development, viral pathogenesis, and atherosclerosis and, thus, represents a potential therapeutic target. TRIM family proteins share a multidomain architecture with a conserved N-terminal TRIM and a variable C-terminal domain. Human TRIM7 contains the canonical TRIM motif and a B30.2 domain at the C terminus. To contribute to the understanding of the mechanism of action of TRIM7, we solved the X-ray crystal structure of its B30.2 domain (TRIM7(B30.2)) in two crystal forms at resolutions of 1.6 A and 1.8 A. TRIM7(B30.2) exhibits the typical B30.2 domain fold, consisting of two antiparallel beta-sheets of seven and six strands, arranged as a distorted beta-sandwich. Furthermore, two long loops partially cover the concave face of the beta-sandwich defined by the beta-sheet of six strands, thus forming a positively charged cavity. We used sequence conservation and mutational analyses to provide evidence of a putative binding interface for GN1. These studies showed that Leu423, Ser499, and Cys501 of TRIM7(B30.2) and the C-terminal 33 amino acids of GN1 are critical for this binding interaction. Molecular dynamics simulations also revealed that hydrogen bond and hydrophobic interactions play a major role in the stability of a modeled TRIM7(B30.2)-GN1 C-terminal peptide complex. These data provide useful information that could be used to target this interaction for the development of potential therapeutic agents.

Automated summary

TRIM7 is an important E3 ubiquitin ligase that plays a role in cancer, viral pathogenesis, and atherosclerosis, making it a potential therapeutic target. It has a structure containing TRIM and B30.2 domains, with the X-ray crystal structure of the B30.2 domain revealing a putative binding interface for GN1. This information could be useful in developing potential therapeutic agents that target this interaction.