Structural studies of TRIM7 B30.2 domain and its interaction with glycogenin

CARRIZO, MARÍA E.; MUÑOZ SOSA, CHRISTIAN J.

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica; 2019

Sociedad Argentina de Biofísica

TRIM family of proteins comprises more than 80 members encoded in the human genome that participate in diverse cellular processes. They share a multimodular architecture with a conserved N-terminal tripartite motif (TRIM) and a variable C-terminal region. The TRIM motif includes a RING (Really Interesting New Gene) finger domain, one or two B-box domains, and a coiled-coil region. The RING finger is a zinc-binding domain that confers E3 ubiquitin ligase activity. B-boxes are also zinc-binding motifs but with a less well characterized function. The coiled-coil domain, instead, is mainly involved in dimerization/oligomerization of TRIM proteins. The C-terminal region can contain one or more domains that appear to mediate the recognition of E3 ubiquitin ligase substrates. The most common of these C-terminal domains is the B30.2, which is present in at least 30 human TRIM family members as well as in other unrelated proteins.Human TRIM7 displays the canonical TRIM motif followed by a B30.2 C-terminal domain. It was first identified in a yeast two-hybrid screen for proteins that interact with glycogenin, the autoglucosyltransferase responsible for the initiation of glycogen biosynthesis. It has also shown to be an E3 ubiquitin ligase that play a key role in the c-Jun/AP-1 activation pathway via Ras. Its depletion reduced c-Jun transcriptional activity while its knockdown decreased the growth of lung tumors driven by Ras. A correlation between increased TRIM7 expression level and tumor size has also been described in hepatocellular carcinoma patients. In addition, recent studies have revealed that TRIM7 promotes glycogen accumulation in skeletal muscle when overexpressed and that it has antiviral properties dependent on its ubiquitin ligase activity and the presence of the B30.2 domain.As these evidences suggest, TRIM7 is gaining increasing interest due to its potential as a therapeutic target. In this regard, B30.2 domain may be particularly important since specificity determinants of many TRIM proteins lie in this domain. In order to contribute to the understanding of TRIM7 mechanisms of action, we have solved the crystal structure of its B30.2 domain. Here we present the structural characterization of this domain and provide evidences for a putative binding interface through the analysis of sequence conservation and the effect of different mutations on the interaction with glycogenin, so far the only protein known to interact with TRIM7 B30.2 domain.