Abstract
Tripartite motif (TRIM) proteins are RING E3 ubiquitin ligases defined by a shared domain structure. Several of them are implicated in rare genetic diseases, and mutations in TRIM32 and TRIM-like malin are associated with Limb-Girdle Muscular Dystrophy R8 and Lafora disease, respectively. These two proteins are evolutionary related, share a common ancestor, and both display NHL repeats at their C-terminus. Here, we revmniew the function of these two related E3 ubiquitin ligases discussing their intrinsic and possible common pathophysiological pathways.
Highlights
The post-translational modification of proteins with the small peptide ubiquitin can regulate target protein turnover, subcellular localization, or activity, depending on the topology of the ubiquitin chain built on the substrate
These data would suggest that TRIM32 plays a role in maintaining the homeostasis of both muscles and motor neurons, and its mutations lead to progressive degeneration of the neuromuscular system
Regarding the C-terminal NHL repeats, no structural data is available for either protein, but the high sequence similarity between TRIM32 and malin would suggest that the NHL domain presents a similar three-dimensional structure
Summary
The post-translational modification of proteins with the small peptide ubiquitin can regulate target protein turnover, subcellular localization, or activity, depending on the topology of the ubiquitin chain built on the substrate. Given these broad effects, the process occurs through a tightly regulated enzymatic cascade. The type of chain that is formed, its length, and the type of residue of the substrate targeted with the poly-ubiquitin chain will influence the pathway undertaken by the modified substrate [5] It is well-established that proteins with K48-linked poly-ubiquitin chains are directed to proteasomal degradation, while K63-linked poly-ubiquitin chains are involved in the regulation of processes such as DNA repair, protein trafficking, or RNA translation [6,7]. Targeting different Ub lysines or Met for chain formation allows the generation of a great variety of distinct Ub modifications, including different homotypic chains, and mixed and branched chains
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