Crystal structure of PRY‐SPRY domain of human TRIM72

Abstract

Tripartite motif-containing (TRIM) family proteins consist of multimodular domains including a relatively conserved N-terminal RBCC domain consisting of a RING finger for E3 ubiquitin ligase activity, a zinc-bound B-box for protein–protein interaction, one or two coiledcoil domains for oligomerization, and a variable C-terminal domain. In some cases, however, TRIM proteins have a PRY-SPRY domain (PRY segment followed SPRY domain identified in a Dictyostelium discoidueum kinase splA and mammalian Ca-release channels ryanodine receptors) at their C-terminus, which has been identified as a targeting module.1,2 More than 70 members of this family have been identified and characterized, and show a very similar domain architecture; however, their cellular functions are extremely diverse, and include roles in cell proliferation, differentiation, development, oncogenesis, apoptosis, and retroviral replication.1,2 The E3 ligase activity of several TRIM proteins has been previously demonstrated, as they usually harbor a RING domain at the N-terminal region. Each TRIM protein interacts with distinct targets, which are critical in the aforementioned cellular processes.3–8 Therefore, relatively newly and incompletely characterized C-terminal domains, including the PRY-SPRY domain, are believed to be a central mediator for selective interaction with their partners. Well-studied members of the TRIM family include the following: TRIM1, TRIM5a, TRIM19, and TRIM22, which target retroviruses and prevent their replication inside cells3,6; TRIM18/MID1 and TRIM20/pyrin, which are linked to Opitz G/BBB syndrome and familial Mediterranean fever, respectively2,9; TRIM21/Ro52, which is a major autoantigen in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Sjorgen’s syndrome10,11; and TRIM63/Murf1, TRIM55/ Murf2, TRIM41, and TRIM32, which function in muscle cells.1,12 Recently, another TRIM family protein, TRIM72/MG53 has been shown to be expressed specifically in skeletal muscle and heart, and also been demonstrated to perform a critical function in membrane repair following acute muscle injury.13–15 Human TRIM72 consists of 477 amino acid residues with the standard domain organization of the TRIM family [Fig. 1(A)]. By way of contrast with the RBCC domain, which is predictive of its molecular function, very little is currently known regarding the PRY-SPRY domain, or how it has evolved to mediate diverse functions in each TRIM protein. Thus far, two structures of the SPRY domain have been determined in the complex state; however, their interac-