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

Muñoz Sosa et al. J Biol Chem. 2021

TRIM7 is an E3 ubiquitin ligase that was first identified through its interaction with glycogenin-1, 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 tripartite motif (TRIM) and a variable C-terminal domain. Human TRIM7 contains the canonical TRIM motif and a B30.2 domain at the C-terminus. In order 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 Å and 1.8 Å. TRIM7^B30.2 exhibits the typical B30.2 domain fold, consisting of two antiparallel β-sheets of seven and six strands, arranged as a distorted β-sandwich. Furthermore, two long loops partially cover the concave face of the β-sandwich defined by the β-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 glycogenin-1. These studies showed that Leu423, Ser499 and Cys501 of TRIM7^B30.2, and the C-terminal 33 amino acids of glycogenin-1 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-glycogenin-1 C-terminal peptide complex. These data provide useful information that can be used to target this interaction for the development of potential therapeutic agents.

Autores: Muñoz Sosa CJ, Issoglio FM, Carrizo ME.

Artículo: Crystal structure and mutational analysis of the human TRIM7 B30.2 domain provide insights into the molecular basis of its binding to glycogenin-1. Muñoz Sosa CJ, Issoglio FM, Carrizo ME. J Biol Chem. 2021 May 11:100772. doi: 10.1016/j.jbc.2021.100772. Online ahead of print.