Identification of RING E3 pseudoligases in the TRIM protein family

Abstract

TRIpartite Motif (TRIM) family proteins have diverse roles across a broad variety of cellular functions, which are largely presumed to depend on their ubiquitin E3 ligase activity, conferred by a RING domain. However, recent reports have shown that some TRIMs lack detectable ubiquitination activity in isolation, despite containing a RING domain. Here, we present parallel in cellulo, in vitro, and in silico structure-function analyses of the ubiquitin E3 ligase activity and RING domain structural characteristics of whole TRIM protein family. In-depth follow-up studies of this comprehensive dataset reveals a number of pseudoligases, whose RING domains have structurally diverged at either the homodimerisation or E2[~]ubiquitin interfaces, thereby disrupting their ability to catalyse ubiquitin transfer. Together, these data raise intriguing open questions regarding the unknown TRIM functions in physiology and disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/614675v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@7c851org.highwire.dtl.DTLVardef@f06afdorg.highwire.dtl.DTLVardef@3cd7org.highwire.dtl.DTLVardef@19a60e6_HPS_FORMAT_FIGEXP M_FIG C_FIG